bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic ASPM Is a Regulatory Hub of Developmental and Stemness Signaling in Cancers
Authors: Tsai Kelvin K. , Bae Byoung-Il , Hsu Chung-Chi , Cheng Li-Hsin , Shaked Yuval 
Published: June 2023

Abstract
Despite recent advances in molecularly targeted therapies and immunotherapies, the effective treatment of advanced-stage cancers remains a largely unmet clinical need. Identifying driver mechanisms of cancer aggressiveness can lay the groundwork for the development of breakthrough therapeutic strategies. Assembly factor for spindle microtubules (ASPM) was initially identified as a centrosomal protein that regulates neurogenesis and brain size. Mounting evidence has demonstrated the pleiotropic roles of ASPM in mitosis, cell-cycle progression, and DNA double-strand breaks (DSB) repair. Recently, the exon 18–preserved isoform 1 of ASPM has emerged as a critical regulator of cancer stemness and aggressiveness in various malignant tumor types. Here, we describe the domain compositions of ASPM and its transcript variants and overview their expression patterns and prognostic significance in cancers. A summary is provided of recent progress in the molecular elucidation of ASPM as a regulatory hub of development- and stemness-associated signaling pathways, such as the Wnt, Hedgehog, and Notch pathways, and of DNA DSB repair in cancer cells. The review emphasizes the potential utility of ASPM as a cancer-agnostic and pathway-informed prognostic biomarker and therapeutic target.
Impact of Frontline Ivosidenib on Volumetric Growth Patterns in Isocitrate Dehydrogenase–mutant Astrocytic and Oligodendroglial Tumors
Authors: Kamson David Olayinka , Puri Sushant , Sang Yingying , Shi Meihui Jessica , Blair Lindsay , Blakeley Jaishri O. , Laterra John 
Published: June 2023

Abstract

Purpose:
Isocitrate dehydrogenase (IDH)-mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients’ most productive years. We report our experience using off-label first-in-class mutant IDH1 inhibitor ivosidenib and its impact on tumor volume in IDH-mutant gliomas.

Experimental Design:
We retrospectively analyzed patients ages ≥18 years with radiation/chemotherapy-naïve, mutant IDH1, nonenhancing, radiographically active, grade 2/3 gliomas, and ≥2 pretreatment and ≥2 on-treatment ivosidenib MRIs. T2/FLAIR-based tumor volumes, growth rates, and progression-free survival (PFS) were analyzed. log-linear mixed-effect modeling of growth curves adjusted for grade, histology, and age was performed.

Results:
We analyzed 116 MRIs of 12 patients [10 males, median age 46 years (range: 26–60)]: 8 astrocytomas (50% grade 3) and 4 grade 2 oligodendrogliomas. Median on-drug follow-up was 13.2 months [interquartile range (IQR): 9.7–22.2]. Tolerability was 100%. A total of 50% of patients experienced ≥20% tumor volume reduction on-treatment and absolute growth rate was lower during treatment (−1.2 ± 10.6 cc/year) than before treatment (8.0 ± 7.7 cc/year; P ≤ 0.05). log-linear models in the Stable group (n = 9) showed significant growth before treatment (53%/year; P = 0.013), and volume reduction (−34%/year; P = 0.037) after 5 months on treatment. After treatment, volume curves were significantly lower than before treatment (after/before treatment ratio 0.5; P &lt; 0.01). Median time-to-best response was 11.2 (IQR: 1.7–33.4) months, and 16.8 (IQR: 2.6–33.5) months in patients on drug for ≥1 year. PFS at 9 months was 75%.

Conclusions:
Ivosidenib was well tolerated and induced a high volumetric response rate. Responders had significant reduction in tumor growth rates and volume reductions observed after a 5-month delay. Thus, ivosidenib appears useful to control tumor growth and delay more toxic therapies in IDH-mutant nonenhancing indolently growing gliomas.
See related commentary by Lukas and Horbinski, p. 4709
Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1
Authors: Kamhieh-Milz Julian , Chen Lei , Goettsch Claudia , Pfefferkorn Anna Maria , Hofmann Anja , Brunssen Coy , Müller Gregor M. , Walther Thomas , Ashraf Muhammad Imtiaz , Moll Guido , Morawietz Henning , Witowski Janusz , Catar Rusan 
Published: June 2023

BACKGROUND:
Increasing evidence suggests that superoxide ions produced by NOX (nicotinamide adenine dinucleotide phosphate oxidases) mediate vascular effects of Ang II (angiotensin II) evoked by atherogenic diets. Here, we analyzed the mechanism by which NOX2 contributes to Ang II–induced ET-1 (endothelin 1) production in human microvascular endothelial cells.

METHODS:

The effects of high-fat diet were compared between WT (wild type) and
Nox2
(
mouse NOX2 gene
)-deficient mice. ET-1 production and NOX2 expression by human microvascular endothelial cells in vitro were analyzed by ELISA, reverse transcription quantitative polymerase chain reaction, electrophoretic mobility shift assay, promoter deletions, RNA interference, and pharmacological inhibition. Production of superoxide anions was visualized by fluorescent cell labeling.

RESULTS:

Feeding mice high-fat diet for 10 weeks increased cardiac expression and plasma levels of Ang II and ET-1 in WT but not in
Nox2
-deficient animals. Exposure of human microvascular endothelial cells to Ang II resulted in increased ET-1 production, which could be blocked by silencing
NOX2
(
human NOX2 gene
). Ang II promoted
NOX2
expression through induction of the Oct-1 (human/mouse octamer binding transcription factor 1 protein) and activation of the
NOX2
promoter region containing Oct-1–binding sites. Stimulation of
NOX2
expression by Ang II was associated with increased production of superoxide anions. Inhibition of Oct-1 by small interfering RNA reduced Ang II–induced
NOX2
expression and superoxide anion production, and neutralization of superoxide by SOD (superoxide dismutase) abolished Ang II–stimulated
ET1
(
human ET-1 gene
) promoter activity, ET1 mRNA expression, and ET-1 release.

CONCLUSIONS:
Ang II may promote ET-1 production in the endothelium in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2.
Localized Prox1 Regulates Aortic Valve Endothelial Cell Diversity and Extracellular Matrix Stratification in Mice
Authors: O’Donnell Anna , Gonzalez Brittany A. , Mukherjee Shreyasi , Wilson Ruby , Alfieri Christina M. , Swoboda Casey O. , Millay Douglas P. , Zorn Aaron M. , Yutzey Katherine E. 
Published: June 2023

BACKGROUND:
Specialized valve endothelial cell (VEC) populations are localized oriented to blood flow in developing aortic and mitral valves, but their roles in valve development and disease are unknown. In the aortic valve (AoV), a population of VECs on the fibrosa side expresses the transcription factor Prox1 together with genes found in lymphatic ECs. In this study, we examine Prox1’s role in regulating a lymphatic-like gene network and promoting VEC diversity required for the development of the stratified trilaminar extracellular matrix (ECM) of murine AoV leaflets.

METHODS:

To determine whether disruption of Prox1 localization affects heart valve development, we generated mice (

NFATc1
enCre

Prox1
gain-of-function) in which Prox1 is overexpressed on the ventricularis side of the AoV beginning in embryonic development. To identify potential targets of Prox1, we performed cleavage under targets and release using nuclease on wild-type and

NFATc1
enCre

Prox1
gain-of-function AoVs with validation by colocalization in vivo using RNA in situ hybridization in

NFATc1
enCre

Prox1
gain-of-function AoVs. Natural induction of Prox1 and target gene expression was evaluated in myxomatous AoVs in a mouse model of Marfan syndrome (

Fbn1
C1039G/+

).

RESULTS:

The overexpression of Prox1 is sufficient to cause enlargement of AoVs by postnatal day (P)0, as well as a decrease in ventricularis-specific gene expression and disorganized interstitial ECM layers at P7. We identified potential targets of Prox1 known to play roles in lymphatic ECs including
Flt1
,
Efnb2
,
Egfl7
, and
Cx37
. Ectopic Prox1 colocalized with induced
Flt1
,
Efnb2
, and
Cx37
expression in

NFATc1
enCre

Prox1
gain-of-function AoVs. Moreover, in Marfan syndrome myxomatous AoVs, endogenous Prox1, and its identified targets, were ectopically induced in ventricularis side VECs.

CONCLUSIONS:
Our results support a role for Prox1 in localized lymphatic-like gene expression on the fibrosa side of the AoV. Furthermore, localized VEC specialization is required for development of the stratified trilaminar ECM critical for AoV function and is dysregulated in congenitally malformed valves.
Clinical Variation in the Treatment Practices for Patients With Type 2 Diabetes: A Cross‐Sectional Patient Simulation Study Among Primary Care Physicians and Cardiologists
Authors: De Belen Enrico , Ganesan Divya , Paculdo David , Gill Rosalynn , Peabody John W. 
Published: June 2023

Background
Cardiovascular disease risk stratification is necessary and critically important in patients with type 2 diabetes. Despite its known benefits to guide treatment and prevention, we hypothesized that providers do not routinely incorporate this into their diagnostic and treatment decisions.

Methods and Results

The QuiCER DM (QURE CVD Evaluation of Risk in Diabetes Mellitus) study enrolled 161 primary care physicians and 80 cardiologists. Between March 2022 and June 2022, we measured the care variation in risk determination among these providers caring for simulated patients with type 2 diabetes. We found a wide variation in the overall assessment of cardiovascular disease in patients with type 2 diabetes. Participants performed half of the necessary care items with quality‐of‐care scores, ranging between 13% and 84%, averaging 49.4±12.6%. Participants did not assess cardiovascular risk in 18.3% of cases and incorrectly stratified risk in 42.8% of cases. Only 38.9% of participants arrived at the correct cardiovascular risk stratification. Those who correctly identified a cardiovascular risk score were significantly more likely to order nonpharmacologic treatments, advising on their patients' nutrition (38.8% versus 29.9%,
P
=0.013) and the correct glycated hemoglobin target (37.7% versus 15.6%,
P
<0.001). Pharmacologic treatments, however, did not vary between those who correctly specified risk and those who did not.

Conclusions
Physician participants struggled to determine the correct cardiovascular disease risk and specify the appropriate pharmacologic interventions in simulated patients with type 2 diabetes. Additionally, there was a wide variation in the quality of care regardless of risk level, indicating opportunities to improve risk stratification.
Left Ventricular Physiology and Ventricular‐Vascular Interactions in Young Patients After Heart Transplantation
Authors: Latus Heiner , Raap Ramona , Klingel Karin , Happel Christoph , Moysich Axel , Khalil Markus , Kerst Gunter , Milla Jakob , Skrzypek Susanne , Thul Josef , Jux Christian , Schranz Dietmar , Apitz Christian 
Published: June 2023

Background
In patients after heart transplantation, systemic arterial hypertension and enhanced central aortic stiffness contribute to increased ventricular afterload, which might lead to graft dysfunction. The aim of our study was to characterize systemic arterial elastance and its impact on left ventricular function and ventriculo‐arterial coupling in a cohort of children, adolescents, and young adults after heart transplantation using invasive conductance catheter technique.

Methods and Results

Thirty patients who had heart transplants (age, 20.0±6.5 years, 7 female) underwent invasive cardiac catheterization including pressure‐volume loop analysis. Load‐independent parameters of systolic (ventricular elastance [Ees]) and diastolic (ventricular compliance) function as well as systemic arterial elastance (Ea, end‐systolic pressure/stroke volume) and ventriculo‐arterial coupling (Ea/Ees) were assessed at baseline level and during dobutamine infusion (10 μg/kg/min). Ees showed an appropriate increase under inotropic stimulation from 0.43 (0.11–2.52) to 1.00 (0.20–5.10) mm Hg/mL/m
2
(
P
<0.0001), whereas ventricular compliance remained rather unchanged (0.16±0.10 mm Hg/mL/m
2
to 0.12±0.07 mm Hg/mL/m
2
;
P
=0.10). Ventriculo‐arterial coupling Ea/Ees was abnormal at rest and did not improve significantly under dobutamine (1.7 [0.6–6.7] to 1.3 [0.5–4.9],
P
=0.70) due to a simultaneous rise in Ea from 0.71 (0.37–2.82) to 1.10 (0.52–4.03) mm Hg/mL/m
2
(
P
<0.0001). Both Ees and ventricular compliance were significantly associated with Ea at baseline and under dobutamine infusion.

Conclusions
Patients who underwent heart transplantation show impaired ventriculo‐arterial coupling at rest and under inotropic stimulation despite preserved left ventricular contractile reserve. An abnormal response in vascular function resulting in increased afterload seems to represent an important factor that may play a role for the development of late graft failure.
Pupil Size Encodes Uncertainty during Exploration
Authors: Fan Haoxue , Burke Taylor , Sambrano Deshawn Chatman , Dial Emily , Phelps Elizabeth A. , Gershman Samuel J. 
Published: June 2023

Abstract
Exploration is an important part of decision making and is crucial to maximizing long-term rewards. Past work has shown that people use different forms of uncertainty to guide exploration. In this study, we investigate the role of the pupil-linked arousal system in uncertainty-guided exploration. We measured participants' (n = 48) pupil dilation while they performed a two-armed bandit task. Consistent with previous work, we found that people adopted a hybrid of directed, random, and undirected exploration, which are sensitive to relative uncertainty, total uncertainty, and value difference between options, respectively. We also found a positive correlation between pupil size and total uncertainty. Furthermore, augmenting the choice model with subject-specific total uncertainty estimates decoded from the pupil size improved predictions of held-out choices, suggesting that people used the uncertainty estimate encoded in pupil size to decide which option to explore. Together, the data shed light on the computations underlying uncertainty-driven exploration. Under the assumption that pupil size reflects locus coeruleus-norepinephrine neuromodulatory activity, these results also extend the theory of the locus coeruleus-norepinephrine function in exploration, highlighting its selective role in driving uncertainty-guided random exploration.
Rural Administration, Tax-Farming, and the mutadarriks in Egypt from the Late 14th to the Early 16th Centuries
Authors: Igarashi Daisuke 
Published: June 2023

Abstract
This paper focuses on the category of Egyptian provincial officials called mutadarrik who emerged in the late 14th century, to understand the relationship between the government and rural areas, and the state of rural society in late medieval Egypt. After the mid-14th century, the iqṭāʿ land system underwent a major transformation. Amidst repeated plagues, declining agricultural production, rampant political instability, and the rise of Arab tribes in the provinces, the financial and local administrations of the Mamluk Sultanate underwent a substantial process of restructuring. This paper shows that the emergence of the mutadarrik was closely related to these changes in the administration as well as in rural society.
Place without an Owner: Urban Modernization and Waqf Property in post-Ottoman Niš
Authors: Radovanović Jelena 
Published: June 2023

Abstract
This article takes the example of post-Ottoman Niš to argue that the transformation of post-Ottoman cities was not a local, nationalism-induced architectural phenomenon, as suggested by the studies of “de-Ottomanization,” but rather a global development which was made possible through the dismantling of the local Ottoman legal regime of urban property. Focusing on the waqf as a quintessential Ottoman form of urban property, this article examines how war and displacement of the Muslim population on the one hand, and new associations between the modern city and particular forms of property on the other together contributed to the destruction of the waqf despite its protection by international law.
‘Do You Not Bow before Heaven?’: The First Qing- Durrānī Encounter, the Tributary Non-relationship, and Disorder on a Shared Frontier
Authors: Eijk Juul , Khan Timur 
Published: June 2023

Abstract
In 1763, Aḥmad Shāh Durrānī sent an embassy to the Qianlong emperor. The envoy caused offence by refusing to prostrate himself. Still, the Qing court fêted his embassy. It seemed the beginning of a promising relationship, but the two empires never had contact again. The Qing court presented the embassy as a tributary mission, but in the pragmatic world of Qing frontier policy, contact with the Durrānīs was deliberately avoided. Why did no relationship develop? This attitude stemmed from Qianlong’s distrust of Central Asian rulers, and his understanding of the Afghans not as a tributary, but a rival imperial power.
Twig-assisted masturbation in Balinese long-tailed macaques
Authors: Cenni Camilla , Wandia I Nengah , Leca Jean-Baptiste 
Published: June 2023

Abstract
We documented evidence of idiosyncratic but repeated twig-assisted genital stimulation by Balinese long-tailed macaques (Macaca fascicularis), living in Ubud, Indonesia. This population is known to customarily engage in genital stone-tapping/-rubbing, a behaviour expressed by males and females of different age classes as part of a broader cultural repertoire of stone-directed and overall playful actions known as stone handling. However, genital stimulation using other objects has never been reported in this population and species. We observed repeated and extensive twig-assisted genital stimulation in one adult female and one adult male. We also recorded three instances of twig-assisted genital stimulation in three additional individuals. Our results indicate that this behaviour is not accidental and may be sexually motivated; that is, it may be another form of tool-assisted masturbation in this primate population. This report provides a valuable addition to the increasing literature on tool-assisted behavioural innovations pertaining to self-care and possibly pleasure.
“Strictness is a Virtue” – Social Determination of Authoritarian Parenting and Political Authoritarianism
Authors: Zhussipbek Galym , Nagayeva Zhanar 
Published: June 2023

Abstract
Parenting and children’s rights are intimately related. The parenting styles characterised by low responsiveness to children’s needs, including authoritarian-paternalistic and those of neglect, are harmful to child’s development and contradict the main principles of children’s rights. The slow development of children’s rights in Kazakhstan and, in general, in the Eurasian1 context, derives from the social norms justifying authoritarian-paternalistic parenting, specifically, the widespread belief that “strictness is a virtue”. This article proposes and discusses the concepts of “social determination of authoritarian parenting” and “social determination of political authoritarianism”. The former concept denotes an embodiment of social norms that shape the parenting styles with low responsiveness to children’s needs, especially authoritarian-paternalistic. The latter suggests that authoritarianism is a product of social and cultural contexts, including parenting. These concepts, being mutually supportive phenomena, create the vicious circle of the persistency of authoritarianism in both politics and in child-rearing.
Redefining Inclusive Education for Autistic Children in International and European Law
Authors: Ducarre Lucie Margot 
Published: June 2023

Abstract
This paper focuses on the legal concept of inclusive education, and the challenges that its current interpretation raises, especially for autistic children. Centring on European and international law, it first analyses the sources and genesis of the current interpretation of inclusive education as full mainstream inclusion. It then proceeds critically to examine the conceptual and legal limitations this interpretation involves, before developing arguments for a more neurodiverse and rights-based alternative. Under this new interpretation, states would be required not only to render mainstream education more inclusive, but also to provide alternative educational offers for when mainstream education is not able to provide a neurodiverse and rights-based inclusive education.
Groundwater–rock interactions in crystalline rocks: evidence from SIMS oxygen isotope data
Authors: Yardley Bruce W.D. , Milodowski Antoni E. , Field Lorraine P. , Wogelius Roy A. , Metcalfe Richard , Norris Simon 
Published: June 2023

AbstractThe diffusive exchange of dissolved material between fluid flowing in a fracture and the enclosing wallrocks (rock matrix diffusion) has been proposed as a mechanism by which radionuclides derived from a radioactive waste repository may be removed from groundwater and incorporated into the geosphere. To test the effectiveness of diffusive exchange in igneous and metamorphic rocks, we have carried out an investigation of veins formed at low temperatures (<100°C), comparing the oxygen isotopic composition of vein calcite with that of secondary calcite in the wallrocks. Two examples of veins from the Borrowdale Volcanic Group, Cumbria, and one from the Mountsorrel Granodiorite, Leicestershire, UK, have remarkably similar vein calcite compositions, ca. +20‰(SMOW) or greater, substantially heavier than the probable compositions of the host rocks, and these vein calcite compositions are inferred to reflect the infiltrating fluid and the temperature of vein formation. Calcites from the wallrocks are similar to those in veins, with little evidence for exchange with the wallrocks. The results support existing models for this type of vein which suggest low-temperature growth from formation brines originally linked to Permian or Triassic evaporites. The results are consistent with flow through fractures being attenuated through a damage zone adjacent to the fracture and provide no evidence of diffusional exchange with pore waters from wallrocks.