bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world patient-reported outcomes and concordance between patient and physician reporting of side effects across lines of therapy in multiple myeloma within the USA
Authors: Ribbands Amanda , Boytsov Natalie , Bailey Abigail , Gorsh Boris , Luke Emily , Lambert Annabel 
Published: June 2023

Abstract
Purpose
We aimed to explore patient-reported outcomes (PROs) and patient and physician concordance of side effects perception across lines of therapy (LOT) in multiple myeloma (MM) within the United States of America (USA).

Methods
Data were drawn from the Adelphi Real World MM III Disease Specific Programme™, a point-in-time survey of hemato-oncologists/hematologists and their patients with MM conducted in the USA between August 2020 and July 2021. Physicians reported patient characteristics and side effects. Patients reported side-effect bother and health-related quality of life (HRQoL) using validated PRO tools (European Organisation for the Research and Treatment of Cancer Quality of Life Core Questionnaire/-MM Module [EORTC QLQ-C30/-MY20], EQ-5D-3L and Functional Assessment of Cancer Therapy—General Population physical item 5). Descriptive, linear regression and concordance analyses were performed.

Results
Records from 63 physicians and 132 patients with MM were analyzed. EORTC QLQ-C30/-MY20 and EQ-5D-3L scores were consistent across LOTs. Scores tended to be worse with higher side-effect bother; patients “very much” bothered by side effects had lower median (interquartile range) global health status scores (33.3 [25.0–50.0]) than those “not at all” bothered (79.2 [66.7–83.3]). Patient and physician concordance on side-effect reporting was poor to fair. Patients frequently reported fatigue and nausea as bothersome side effects.

Conclusion
HRQoL of patients with MM was worse with greater side-effect bother. Discordant patient and physician reporting of side effects indicated a need for improved communication during management of MM.
Late Alpine multistage exhumation of the northwestern Rhodope Metamorphic Complex (northern Rila Mountains, Bulgaria)
Authors: Kounov Alexandre , Gerdjikov Ianko , Antić Milorad D. , Georgiev Neven , Spikings Richard A. 
Published: June 2023

AbstractThe Rhodope crystalline massif is an Alpine metamorphic complex exposed across several mountain ranges in southern Bulgaria and northern Greece which has experienced a complex history including continental collision, partial subduction and syn-metamorphic nappe stacking followed by syn- to post-contractional extension. We present new40Ar/39Ar and fission-track data from samples taken from both sides of the North Rhodopean Detachment that were combined with detailed structural studies to investigate the tectonothermal evolution of the northern Rila Mountains. A migmatite from the hanging wall of the North Rhodopean Detachment yields a40Ar/39Ar muscovite age of 100.79 ± 0.55 Ma, a zircon fission-track age of 38.6 ± 1.9 Ma, and an apatite fission-track age of 21.4 ± 1.5 Ma. A biotite schist from the footwall of the detachment yields40Ar/39Ar biotite age of 34.90 ± 0.15 Ma, and zircon and apatite fission-track ages of 35.6 ± 5.6 and 13.3 ± 1.1 Ma, respectively. Our new data give evidence of a multistage exhumation of the study area. Late Early Cretaceous (~ 101 ± 0.6 Ma) cooling of the Variscan high-grade metamorphic basement through 440–400 °C was caused by either erosion of the emplacing thrust sheet, or post-contractional denudation. Fast exhumation along the North Rhodopean Extensional System drove a pulse of increased tectonic denudation and cooling during the Eocene (39–35 Ma). Exhumation of the rocks in the northern part of the Rila Mountains below 110 ± 10 °C during the middle–late Miocene was associated with displacement along a system of normal faults.
The Nobel Prize of Physiology or Medicine, 1923: controversies on the discovery of the antidiabetic hormone
Authors: de Leiva-Hidalgo Alberto , de Leiva-Pérez Alejandra 
Published: June 2023

Abstract
Aims
To analyze the main contributions to the discovery of the antidiabetic hormone in the period between 1889, the year in which Oskar Minkowski demonstrated that complete pancreatectomy in dogs caused diabetes, and the year 1923, the date in which the clinical use of insulin was consolidated. A main objective has been to review the controversies that followed the Nobel Prize and to outline the role of the priority rule in Science.

Methods
We have considered the priority rule defined by Robert Merton in 1957, which takes into account the date of acceptance of the report of a discovery in an accredited scientific journal and/or the granting of a patent, complemented by the criteria set out by Ronald Vale and Anthony Hyman (2016) regarding the transfer of information to the scientific community and its validation by it. The awarding of the Nobel Prize in Physiology or Medicine in October 1923 has represented a frame of reference. The claims and disputes regarding the prioritization of the contributions of the main researchers in the organotherapy of diabetes have been analyzed through the study of their scientific production and the debate generated in academic institutions.

Main results and conclusions
(1) According to the criteria of Merton, Vale and Hyman, the priority of the discovery of the antidiabetic hormone corresponds to the investigations developed in Europe by E. Gley (1900), GL Zülzer (1908) and NC Paulescu (1920). (2) The active principle of the pancreatic extracts developed by Zülzer (acomatol), Paulescu (pancreina) and Banting and Best (insulin) was the same. (3) JB Collip succeeded in isolating the active ingredient from the pancreatic extract in January 1922, eliminating impurities to the point of enabling its use in the clinic. (4) In 1972, the Nobel Foundation modified the purpose of the 1923 Physiology or Medicine award to Banting and Macleod by introducing a new wording: "the credit for having produced the pancreatic hormone in a practical available form" (instead of “for the discovery of insulin”).
A report of short-term aversive conditioning on a wolf documented through telemetry
Authors: Zanni Michele , Brivio Francesca , Berzi Duccio , Calderola Sonia , Luccarini Siriano , Costanzi Liliana , Dartora Fabio , Apollonio Marco 
Published: June 2023

AbstractPredation by large predators on livestock is one of the main concerns in species conservation as it elicits prompt and effective retaliations. Therefore, conflict mitigation is essential to ensure long-term coexistence of predators with humans. We performed aversive conditioning (AC) with rubber bullets on one collared wolf that had become particularly bold toward a transhumant shepherd and had preyed on livestock. By exploiting the unique fine-resolution location data available before and after the AC event, alongside careful retrospective field investigations, we were able to analyse the effects of AC on wolf behaviour. Our study revealed that after just a single AC event, the wolf modified its spatial and predatory behaviour: the wolf changed its use of space by increasing distance from humans and ceased to attack farms in the following 2 months; actually, the only livestock preyed after AC was represented by a sheep and two goats lost by shepherds that had left alpine pastures. This study represents a first step to increase knowledge on AC effect on the wolf. Additional researchers are encouraged to conduct and publish findings on this topic in order to provide a useful and widely tested array of tools to promote wolf conservation in human-dominated landscapes.
Comprehensive Analysis of TICRR in Hepatocellular Carcinoma Based on Bioinformatics Analysis
Authors: Chen Jing-Jing , Zhang Lu-Lu , Liu Zhen , Men Wan Qi , Chen Fang , Shen Jilu 
Published: June 2023

AbstractHepatocellular carcinoma (HCC) is one of the leading cause of cancer-associated death in the world. However, due to the complexity of HCC, it is urgent for us to find a reliable and accurate biomarker for HCC gene therapy.TopBP1-interacting checkpoint and replication regulator (TICRR), known as Treslin in vertebrate and sld3 in yeast, is involved in the tumorigenesis, progression, matastasis, diagnosis, and predicting prognosis of HCC. Disappointingly, the mechanism of TICRR expression in HCC is still not described in detail and requires further analysis. In this study, TCGA (www.tcga-data.nci.nih.gov/tcga/) datasets and GEO (www.ncbi.nlm.nih.gov/geo) datasets were used to analyze the expression of TICRR in HCC, the relevance of TICRR mRNA expression and clinicopathological characteristics in patients with HCC, and the relationship between TICRR expression and immune infiltration level in Patients with HCC. Based on MethSurv database, the impact of TICRR in patients with HCC was investigated. In addition, GO/KEGG enrichment analysis of TICRR co-expression was performed using the R package. TICRR was found drastically highly expressed in a variety of cancer types including HCC.ROC curve analysis showed that TICRR had higher accuracy in predicting HCC compared with AFP. The expression level of TICRR was marked positively correlated with tumor stage and prognosis in Patients with HCC.GO/KEGG enrichment analysis showed that TICRR was associated with cell division and cell cycle as well as p53 signaling pathway. In addition, patients with high TICRR methylation of cg05841809, cg09403165, and cg03312532 CpG sites were significantly correlated with poor prognosis of HCC. This study demonstrated that increased TICRR expression in HCC might play an important role in the tumorigenesis, progression, diagnosis, and predicting prognosis of HCC. Therefore, TICRR might be used as a promising diagnostic and prognostic biomarker for HCC gene therapy.
A Cognitive Load Theory Approach to Defining and Measuring Task Complexity Through Element Interactivity
Authors: Chen Ouhao , Paas Fred , Sweller John 
Published: June 2023

AbstractEducational researchers have been confronted with a multitude of definitions of task complexity and a lack of consensus on how to measure it. Using a cognitive load theory-based perspective, we argue that the task complexity that learners experience is based on element interactivity. Element interactivity can be determined by simultaneously considering the structure of the information being processed and the knowledge held in long-term memory of the person processing the information. Although the structure of information in a learning task can easily be quantified by counting the number of interacting information elements, knowledge held in long-term memory can only be estimated using teacher judgment or knowledge tests. In this paper, we describe the different perspectives on task complexity and present some concrete examples from cognitive load research on how to estimate the levels of element interactivity determining intrinsic and extraneous cognitive load. The theoretical and practical implications of the cognitive load perspective of task complexity for instructional design are discussed.
Optimizing treatment of brain metastases in an era of novel systemic treatments: a single center consecutive series
Authors: van Schie P. , Rijksen B. L. T. , Bot M. , Wiersma T. , Merckel L. G. , Brandsma D. , Compter A. , de Witt Hamer P. C. , Post R. , Borst G. R. 
Published: June 2023

Abstract
Background
The multidisciplinary management of patients with brain metastases consists of surgical resection, radiation treatment and systemic treatment. Tailoring and timing these treatment modalities is challenging. This study presents real-world data from consecutively treated patients and assesses the impact of all treatment strategies and their relation with survival. The aim is to provide new insights to improve multidisciplinary decisions towards individualized treatment strategies in patients with brain metastases.

Methods
A retrospective consecutive cohort study was performed. Patients with brain metastases were included between June 2018 and May 2020. Brain metastases of small cell lung carcinoma were excluded. Overall survival was analyzed in multivariable models.

Results
676 patients were included in the study, 596 (88%) received radiotherapy, 41 (6%) awaited the effect of newly started or switched systemic treatment and 39 (6%) received best supportive care. Overall survival in the stereotactic radiotherapy group was 14 months (IQR 5–32) and 32 months (IQR 11–43) in patients who started or switched systemic treatment and initially did not receive radiotherapy. In patients with brain metastases without options for local or systemic treatment best supportive care was provided, these patients had an overall survival of 0 months (IQR 0–1). Options for systemic treatment, Karnofsky Performance Score ≥ 70 and breast cancer were prognostic for a longer overall survival, while progressive extracranial metastases and whole-brain-radiotherapy were prognostic for shorter overall survival.

Conclusions
Assessing prognosis in light of systemic treatment options is crucial after the diagnosis of brain metastasis for the consideration of radiotherapy versus best supportive care.

Graphical Abstract
Evolutionary diversity of proton and water channels on the oxidizing side of photosystem II and their relevance to function
Authors: Hussein Rana , Ibrahim Mohamed , Bhowmick Asmit , Simon Philipp S. , Bogacz Isabel , Doyle Margaret D. , Dobbek Holger , Zouni Athina , Messinger Johannes , Yachandra Vittal K. , Kern Jan F. , Yano Junko 
Published: June 2023

AbstractOne of the reasons for the high efficiency and selectivity of biological catalysts arise from their ability to control the pathways of substrates and products using protein channels, and by modulating the transport in the channels using the interaction with the protein residues and the water/hydrogen-bonding network. This process is clearly demonstrated in Photosystem II (PS II), where its light-driven water oxidation reaction catalyzed by the Mn4CaO5 cluster occurs deep inside the protein complex and thus requires the transport of two water molecules to and four protons from the metal center to the bulk water. Based on the recent advances in structural studies of PS II from X-ray crystallography and cryo-electron microscopy, in this review we compare the channels that have been proposed to facilitate this mass transport in cyanobacteria, red and green algae, diatoms, and higher plants. The three major channels (O1, O4, and Cl1 channels) are present in all species investigated; however, some differences exist in the reported structures that arise from the different composition and arrangement of membrane extrinsic subunits between the species. Among the three channels, the Cl1 channel, including the proton gate, is the most conserved among all photosynthetic species. We also found at least one branch for the O1 channel in all organisms, extending all the way from Ca/O1 via the ‘water wheel’ to the lumen. However, the extending path after the water wheel varies between most species. The O4 channel is, like the Cl1 channel, highly conserved among all species while having different orientations at the end of the path near the bulk. The comparison suggests that the previously proposed functionality of the channels in T. vestitus (Ibrahim et al., Proc Natl Acad Sci USA 117:12624–12635, 2020; Hussein et al., Nat Commun 12:6531, 2021) is conserved through the species, i.e. the O1-like channel is used for substrate water intake, and the tighter Cl1 and O4 channels for proton release. The comparison does not eliminate the potential role of O4 channel as a water intake channel. However, the highly ordered hydrogen-bonded water wire connected to the Mn4CaO5 cluster via the O4 may strongly suggest that it functions in proton release, especially during the S0 → S1 transition (Saito et al., Nat Commun 6:8488, 2015; Kern et al., Nature 563:421–425, 2018; Ibrahim et al., Proc Natl Acad Sci USA 117:12624–12635, 2020; Sakashita et al., Phys Chem Chem Phys 22:15831–15841, 2020; Hussein et al., Nat Commun 12:6531, 2021).
Induction of apoptosis, oxidative stress, hormonal, and histological alterations in the reproductive system of thiamethoxam-exposed female rats
Authors: El-Din Marwa Alaa El-Din Sarry , Ghareeb Abd El-Wahab El , El-Garawani Islam M. , El-Rahman Heba Ali Abd 
Published: June 2023

Abstract
The present study aimed to investigate the oral toxic effects of 1/10 LD50 and 1/5 LD50 of thiamethoxam (TMX), a neonicotinoid insecticide, on the reproductive system of female Wistar rats. Thirty female rats were divided into three groups and supplied orally with either; saline solution, 1/10 LD50 of TMX (156 mg/kg) or 1/5 LD50 of TMX (312 mg/kg). The daily administration was extended for 30 days. Investigating the parameters of oxidative stress, hormonal levels, histopathological alterations, and the apoptotic markers (P53, BAX, BCL-2, and caspase-3) was performed in the uterus and ovary of rats. Results showed significant changes in the body weight gain, and relative weight of the left and right ovaries and uterus. Moreover, luteinizing hormone (LH), estradiol (ED), and progesterone (PG) serum levels were not significantly altered following TMX oral administration. The level of follicle-stimulating hormone in the TMX-exposed group (156 mg/kg) was significantly increased; however, a significant decrease was observed in TMX-exposed animals (312 mg/kg). TMX induced significant oxidative stress in exposed groups by reducing the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), and elevating malondialdehyde (MDA) levels. Following hematoxylin and eosin staining, the microscopic examination revealed deteriorated luteal cells with vacuolation in the corpus luteum, a follicle containing a degenerated oocyte and degeneration/necrosis of the circular muscle layer with a high rate of apoptotic cells in TMX-exposed animals. TMX induced transcriptional alterations in apoptosis-related genes shifting towards the activation of the intrinsic apoptotic pathway. Collectively, results suggest the toxic effect of the TMX on the reproductive health of female Wistar rats.
APEX1 Nuclease and Redox Functions are Both Essential for Adult Mouse Hematopoietic Stem and Progenitor Cells
Authors: Zaunz Samantha , De Smedt Jonathan , Lauwereins Lukas , Cleuren Lana , Laffeber Charlie , Bajaj Manmohan , Lebbink Joyce H. G. , Marteijn Jurgen A. , De Keersmaecker Kim , Verfaillie Catherine 
Published: June 2023

AbstractSelf-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) are carefully controlled by extrinsic and intrinsic factors, to ensure the lifelong process of hematopoiesis. Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein implicated in DNA repair and transcriptional regulation. Although previous studies have emphasized the necessity of studying APEX1 in a lineage-specific context and its role in progenitor differentiation, no studies have assessed the role of APEX1, nor its two enzymatic domains, in supporting adult HSPC function. In this study, we demonstrated that complete loss of APEX1 from murine bone marrow HSPCs (induced by CRISPR/Cas9) caused severe hematopoietic failure following transplantation, as well as a HSPC expansion defect in culture conditions maintaining in vivo HSC functionality. Using specific inhibitors against either the nuclease or redox domains of APEX1 in combination with single cell transcriptomics (CITE-seq), we found that both APEX1 nuclease and redox domains are regulating mouse HSPCs, but through distinct underlying transcriptional changes. Inhibition of the APEX1 nuclease function resulted in loss of HSPCs accompanied by early activation of differentiation programs and enhanced lineage commitment. By contrast, inhibition of the APEX1 redox function significantly downregulated interferon-stimulated genes and regulons in expanding HSPCs and their progeny, resulting in dysfunctional megakaryocyte-biased HSPCs, as well as loss of monocytes and lymphoid progenitor cells. In conclusion, we demonstrate that APEX1 is a key regulator for adult regenerative hematopoiesis, and that the APEX1 nuclease and redox domains differently impact proliferating HSPCs.
Graphical Abstract
Seasonality and mobility of Epipaleolithic groups in the north-east of the Iberian Peninsula: tooth wear analysis of ungulates from Balma del Gai
Authors: Duñó-Iglesias Paulo , Rivals Florent , Lloveras Lluís , Nadal Jordi 
Published: June 2023

AbstractThe aim of this work is to provide evidence about the mobility of hunter-gatherer groups from the north-east of the Iberian Peninsula during the Epipaleolithic, more specifically, those from the Balma del Gai site (Moià, Barcelona, Spain). To do so, a study of the dental meso- and microwear of ungulates hunted by the groups that occupied the Balma del Gai site during the Epipaleolithic was carried out with two main objectives. First, we aimed to determine the diet of the hunted ungulates to reconstruct the habitat in which they lived in the areas near the site through the comparison of the dental microwear patterns with those of extant populations of directly related taxa that inhabited different regions. Second, we aimed to study the variability in the diet of the hunted ungulates to determine the durations of the occupations, and therefore, to characterize the mobility model (forager vs. collector) of the hunter-gatherer groups at Balma del Gai during the Epipaleolithic. The results indicate that the rock shelter was occupied on a seasonal basis. The browsing dietary traits of the red deer at the time of death combined with archaeological evidence suggest that the occupation took place during late summer and especially autumn. This points to a forager mobility pattern for the hunter-gatherer groups of Balma del Gai that could have been present throughout other contemporary human groups of the Mediterranean coast and pre-coastal area.
Equivalent characterizations of martingale Hardy–Lorentz spaces with variable exponents
Authors: Weisz Ferenc 
Published: June 2023

AbstractWe prove that under the log-Hölder continuity condition of the variable exponent $$p(\cdot )$$

p
(
·
)

, a new type of maximal operators, $$U_{\gamma ,s}$$

U

γ
,
s

is bounded from the variable martingale Hardy–Lorentz space $$H_{p(\cdot ),q}$$

H

p
(
·
)
,
q

to $$L_{p(\cdot ),q}$$

L

p
(
·
)
,
q

, whenever $$0<p_-\le p_+ <\infty $$

0
<

p
-

≤

p
+

<
∞

, $$0<q \le \infty $$

0
<
q
≤
∞

, $$0<\gamma ,s<\infty $$

0
<
γ
,
s
<
∞

and $$1/p_- - 1/p_+ < \gamma +s$$

1
/

p
-

-
1
/

p
+

<
γ
+
s

. Moreover, the operator $$U_{\gamma ,s}$$

U

γ
,
s

generates equivalent quasi-norms on the Hardy–Lorentz spaces $$H_{p(\cdot ),q}$$

H

p
(
·
)
,
q

.
Design-oriented study on target station for spallation neutron source at KOMAC
Authors: Lee Pilsoo , Kang Namwoo , Jang Yongsik 
Published: June 2023

AbstractA neutron-production target system, composed of targets, moderators, reflectors, and shielding, has been conceptually designed for the future MW-class spallation neutron source based on a high-intensity proton accelerator at KOMAC. For targetry, we tentatively adopted a fixed-metal target concept; tantalum-clad tungsten plates in a water-cooled target shroud made of stainless steel. In the thermal analysis and stress calculations using ANSYS, the von Mises stress was found to exceed the yield stress of SS316L at the edges of the structure for a 500-kW proton beam on target. Relatively high stress at edges seems to be a stress concentration that could be reduced by minor design modifications. Preliminary calculation results for a conservative design of target shielding show that radiation dose after the outermost shielding could be lower than 10 $$\upmu$$
μ
Sv/h in a 500-kW operation condition, implying that the design could be optimized to reduce construction costs without loss of shielding performance.