bluuebunny/crossref_metadata_2025_split huggingface dataset:
A grammatical description of the placeholder are in spontaneous Japanese
Authors: SERAKU Tohru , PARK Min-Young , SAKAGUCHI Sayaka 
Published: April 2021

Abstract
When a speaker encounters a word-formulation problem in interaction, she may use a placeholder to saturate the syntactic slot of the target expression in the unfolding sentence. Japanese exhibits the placeholder are, which is assumed to derive from the demonstrative are ‘that.’ Despite rich studies on placeholders, no serious attention has been paid to grammatical parallelism and differences between a placeholder and its original lexical counterpart. In this paper, we focus on the nominal placeholder are (and its predicative variants) and the demonstrative are ‘that,’ and propose the set of criteria which capture their parallelism and differences in non-discrete terms.
The cost-effectiveness of gene therapy for severe hemophilia B: a microsimulation study from the United States perspective
Authors: Bolous Nancy S. , Chen Yichen , Wang Huiqi , Davidoff Andrew M. , Devidas Meenakshi , Jacobs Timothy W. , Meagher Michael M. , Nathwani Amit C. , Neufeld Ellis J. , Piras Bryan A. , Rodriguez-Galindo Carlos , Reiss Ulrike M. , Bhakta Nickhill 
Published: April 2021

Abstract
Adeno-associated virus (AAV)-mediated gene therapy is a novel treatment promising to reduce morbidity associated with hemophilia. Although multiple clinical trials continue to evaluate efficacy and safety, limited cost-effectiveness data have been published. This study compared the potential cost-effectiveness of AAV-mediated factor IX (FIX)-Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX replacement and primary FIX prophylaxis, using either standard or extended half-life FIX products. A microsimulation Markov model was constructed, and transition probabilities between health states and utilities were informed by using published data. Costs were aggregated by using a microcosting approach. A time horizon from 18 years old until death, from the perspective of a third-party payer in the United States, was conducted. Gene therapy was more cost-effective than both alternatives considering a $150 000/quality-adjusted life-year threshold. The price for gene therapy was assumed to be $2 000 000 in the base case scenario; however, one of the 1-way sensitivity analyses was conducted by using observed manufacturing, administration, and 5-year follow-up costs of $87 198 for AAV-mediated gene therapy vector as derived from the manufacturing facility and clinical practice at St Jude Children’s Research Hospital. One-way sensitivity analyses revealed 10 of 102 scenarios in which gene therapy was not cost-effective compared with alternative treatments. Notably, gene therapy remained cost-effective in a hypothetical scenario in which we estimated that the discounted factor concentrate price was 20% of the wholesale acquisition cost in the United States. Probabilistic sensitivity analysis estimated gene therapy to be cost-effective at 92% of simulations considering a $150 000/quality-adjusted life-year threshold. In conclusion, based on detailed simulation inputs and assumptions, gene therapy was more cost-effective than on-demand treatment and prophylaxis for patients with severe hemophilia B.
Primary hepatic lymphoma diagnosed using endoscopic ultrasound-guided liver biopsy: a case report
Authors: Nishikawa Kenichiro , Katsuta Koji , Tanaka Syota , Fujibe Kodai , Hattori Aiji , Shiono Yasunori , Oiwa Michiaki , Matsusaki Shimpei 
Published: April 2021

Abstract
Background
Because of the rarity of primary hepatic lymphomas, diagnosis of this disease entity may often be difficult, and performing a liver biopsy is the only way to establish a definitive diagnosis. Recently, endoscopic ultrasound-guided liver biopsy has emerged as a safe technique for obtaining liver tissue. However, there is no report on the use of endoscopic ultrasound-guided liver biopsy for diagnosing primary hepatic lymphomas.

Case presentation
An 85-year-old Asian man was admitted to our hospital because of multiple liver lesions without any identifiable primary tumor or extrahepatic lymphadenopathy. Serum tumor markers, including alpha-fetoprotein, were in the normal range. We provisionally diagnosed the patient with a cancer of unknown primary origin with liver metastases. An endoscopic ultrasound-guided fine needle liver biopsy of the tumor in the left lobe of the liver was performed using a transgastric approach, and histology revealed a primary hepatic lymphoma of a diffuse large B-cell lymphoma type.

Conclusions
Primary hepatic lymphomas are quite rare, and diagnosis is often difficult without performing a biopsy. Endoscopic ultrasound-guided liver biopsy is a useful diagnostic modality even in such cases.
Hemopneumothorax detection through the process of artificial evolution - a feasibility study
Authors: Sommer Adir , Mark Noy , Kohlberg Gavriel D. , Gerasi Rafi , Avraham Linn Wagnert , Fan-Marko Ruth , Eisenkraft Arik , Nachman Dean 
Published: April 2021

AbstractBackgroundTension pneumothorax is one of the leading causes of preventable death on the battlefield. Current prehospital diagnosis relies on a subjective clinical impression complemented by a manual thoracic and respiratory examination. These techniques are not fully applicable in field conditions and on the battlefield, where situational and environmental factors may impair clinical capabilities. We aimed to assemble a device able to sample, analyze, and classify the unique acoustic signatures of pneumothorax and hemothorax.MethodsAcoustic data was obtained with simultaneous use of two sensitive digital stethoscopes from the chest wall of an ex-vivo porcine model. Twelve second samples of acoustic data were obtained from the in-house assembled digital stethoscope system during mechanical ventilation. The thoracic cavity was injected with increasing volumes of 200, 400, 600, 800, and 1000 ml of air or saline to simulate pneumothorax and hemothorax, respectively. The data was analyzed using a multi-objective genetic algorithm that was used to develop an optimal mathematical detector through the process of artificial evolution, a cutting-edge approach in the artificial intelligence discipline.ResultsThe in-house assembled dual digital stethoscope system and developed genetic algorithm achieved an accuracy, sensitivity and specificity ranging from 64 to 100%, 63 to 100%, and 63 to 100%, respectively, in classifying acoustic signal as associated with pneumothorax or hemothorax at fluid injection levels of 400 ml or more, and regardless of background noise.ConclusionsWe present a novel, objective device for rapid diagnosis of potentially lethal thoracic injuries. With further optimization, such a device could provide real-time detection and monitoring of pneumothorax and hemothorax in battlefield conditions.
Research progress in the effects of terahertz waves on biomacromolecules
Authors: Sun Liu , Zhao Li , Peng Rui-Yun 
Published: April 2021

AbstractWith the rapid development of terahertz technologies, basic research and applications of terahertz waves in biomedicine have attracted increasing attention. The rotation and vibrational energy levels of biomacromolecules fall in the energy range of terahertz waves; thus, terahertz waves might interact with biomacromolecules. Therefore, terahertz waves have been widely applied to explore features of the terahertz spectrum of biomacromolecules. However, the effects of terahertz waves on biomacromolecules are largely unexplored. Although some progress has been reported, there are still numerous technical barriers to clarifying the relation between terahertz waves and biomacromolecules and to realizing the accurate regulation of biological macromolecules by terahertz waves. Therefore, further investigations should be conducted in the future. In this paper, we reviewed terahertz waves and their biomedical research advantages, applications of terahertz waves on biomacromolecules and the effects of terahertz waves on biomacromolecules. These findings will provide novel ideas and methods for the research and application of terahertz waves in the biomedical field.
Forest fire and law: an analysis of Turkish forest fire legislation based on Food and Agriculture Organization criteria
Authors: Elvan Osman Devrim , Birben Üstüner , Özkan Ulaş Yunus , Yıldırım Hasan Tezcan , Türker Yavuz Özhan 
Published: April 2021

Abstract
Background
Because of climate and forest vegetation, Turkey has regions (particularly the Mediterranean and Aegean regions) that are vulnerable to forest fires. Approximately 2000 forest fires have occurred every year for the last 20 years, with at least 48% of them caused by humans. This percentage increases to 71% when the rates of fires of unknown causes are included. In this study, legislation on Turkish forest fires was analyzed based on the Food and Agriculture Organization’s (FAO’s) guide, “Forest Fires and the Law.” The guide was prepared by expert lawyers and addresses the basic topics of definitions; institutional setup and interinstitutional coordination planning, monitoring, and assessment; prevention and preparedness; detection and early warning and suppression; participatory and community-based approaches to fire management; fire use; rehabilitation; and law enforcement. The objective of this study was to reveal the current status of Turkish forestry legislation and its practices based on the FAO guide.

Results
According to our analysis, Turkish forestry legislation has followed the FAO criteria 78.1% of the time. It is clear that effective regulations exist, with the Turkish Constitution being the foremost touchstone. The results illustrate that, no matter how strong the legislation is, a deficiency in administrative measures and a lack of public awareness make combating forest fires unsuccessful.

Conclusions
The areas that need to be improved have been determined to be definitions, participatory and community-based approaches to fire management, and creating a fire line. A focus on public participation and the social approach is needed.
Genetic Thyrotropin Regulation of Atrial Fibrillation Risk Is Mediated Through an Effect on Height
Authors: Shi Mingjian , Manouchehri Ali M , Shaffer Christian M , Vaitinadin Nataraja Sarma , Hellwege Jacklyn N , Salem Joe-Elie , Davis Lea K , Simmons Jill H , Roden Dan M , Shoemaker M Benjamin , Ferguson Jane F , Mosley Jonathan D 
Published: April 2021

Abstract

Context
A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms.

Objective
Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk.

Methods
We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH.

Results
Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from –0.12 (SE 0.02) occurrences of AF per SD change in height to –0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association.

Conclusion
The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone–level elevations in later life.
Clinical Adverse Events Associated with Sodium–Glucose Cotransporter 2 Inhibitors: A Meta-Analysis Involving 10 Randomized Clinical Trials and 71 553 Individuals
Authors: Lin Donna Shu-Han , Lee Jen-Kuang , Chen Wen-Jone 
Published: April 2021

AbstractContextSGLT2is are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined adverse events (AEs) associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown.ObjectiveThis meta-analysis aimed to investigate the occurrence of various AEs associated with sodium–glucose cotransporter 2 inhibitors (SGLT2is) and to examine the level of risk of AEs in patients with different underlying diseases.MethodsWe conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library on January 31, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose vs low dose).ResultsOur analysis included 10 eligible studies with a total of 71 553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% CI 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72–0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs 0.96, P = .066).ConclusionThe use of SGLT2is is generally safe. SGLT2is may be associated with increased risks of genital infection but are protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2is lies in the identification of high-risk populations and close surveillance of patients after treatment.
Production of somatic and germline chimeras in the chicken by transfer of early blastodermal cells
Authors: Petitte J. N. , Clark M. E. , Liu G. , Gibbins A. M. Verrinder , Etches R. J. 
Published: April 2021

ABSTRACT
Cells were isolated from stage X embryos of a line of Barred Plymouth Rock chickens (that have black pigment in their feathers due to the recessive allele at the I locus) and injected into the subgerminal cavity of embryos from an inbred line of Dwarf White Leghorns (that have white feathers due to the dominant allele at the I locus). Of 53 Dwarf White Leghorn embryos that were injected with Barred Plymouth Rock blastodermal cells, 6 (11.3 %) were phenotypically chimeric with respect to feather colour and one (a male) survived to hatching. The distribution of black feathers in the recipients was variable and not limited to a particular region although, in all but one case, the donor cell lineage was evident in the head. The male somatic chimera was mated to several Barred Plymouth Rock hens to determine the extent to which donor cells had been incorporated into his testes. Of 719 chicks hatched from these matings, 2 were phenotypically Barred Plymouth Rocks demonstrating that cells capable of incorporation into the germline had been transferred. Fingerprints of the blood and sperm DNA from the germline chimera indicated that both of these tissues were different from those of the inbred line of Dwarf White Leghorns. Bands that were present in fingerprints of blood DNA from the chimera and not present in those of the Dwarf White Leghorns were observed in those of the Barred Plymouth Rocks. It was concluded that cells recovered from the stage X embryo can subsequently contribute to melanocytes derived from the neural crest, to erythrocytes and to germ cells. This technique of blastodermal cell transfer should be useful in developmental studies and may facilitate the production of transgenic poultry either directly or through the establishment of chicken pluripotent stem cell lines in vitro.
CRTF is a novel transcription factor that regulates multiple stages ofDictyosteliumdevelopment
Authors: Mu Xiuqian , Spanos Seth A. , Shiloach Joseph , Kimmel Alan 
Published: April 2021

During aggregation, Dictyostelium establish nanomolar oscillation waves of extracellular cAMP, but as development progresses, cells become responsive to higher, non-fluctuating concentrations of cAMP. The regulation of the promoter responsible for expression of cAMP receptor subtype 1, CAR1, during aggregation reflects these signaling variations. Transcription of CAR1 from the early, aggregation promoter is activated by cAMP pulsing, but is repressed by continuous exposure to micromolar concentrations of cAMP. Deletion and mutation analyses of this promoter had defined an element essential for cAMP-regulated expression, and mobility shift assay, DNA crosslinking and DNase I footprinting experiments had identified a nuclear protein (CRTF) with zinc-dependent sequence binding specificity. In our study, CRTF was purified to homogeneity, peptides were sequenced and full-length cDNAs were obtained. The deduced CRTF protein is ∼100 kDa with a C-terminal, zinc finger-like motif required for DNA binding; CRTF purified from cells, however, represents only a 40 kDa C-terminal fragment that retains DNA-binding activity.As might have been predicted if CRTF were essential for the regulation of CAR1, crtf-null strains fail to develop under standard conditions or to exhibit induced expression of CAR1 or other cAMP-regulated genes. Furthermore, crtf-nulls also fail to sporulate, even under conditions that bypass the dependence on early cAMP signaling pathways. In addition, early developmental events of crtf-null strains could be rescued with exogenous cAMP treatment, constitutive expression of CAR1 or co-development with wild-type cells; however, these treatments were insufficient to promote sporulation. This suggests a cell-autonomous role for CRTF during late development that is separate from its capacity to control CAR1 expression. Finally, ablation of CRTF promotes a precocious induction of certain cAMP-dependent gene expression pathways. We suggest that CRTF may function to help insulate distinct pathways from simultaneous and universal activation by cAMP. CRTF, thus, exhibits multiple complex and independent regulatory functions during Dictyostelium development.
Heart tube patterning inDrosophilarequires integration of axial and segmental information provided by theBithorax Complexgenes andhedgehogsignaling
Authors: Ponzielli Romina , Astier Martine , Chartier Aymeric , Gallet Armel , Thérond Pascal , Sémériva Michel 
Published: April 2021

The Drosophila larval cardiac tube is composed of 104 cardiomyocytes that exhibit genetic and functional diversity. The tube is divided into the aorta and the heart proper that encompass the anterior and posterior parts of the tube, respectively. Differentiation into aorta and heart cardiomyocytes takes place during embryogenesis. We have observed living embryos to correlate morphological changes occurring during the late phases of cardiogenesis with the acquisition of organ function, including functional inlets, or ostiae.Cardiac cells diversity originates in response to two types of spatial information such that cells differentiate according to their position, both within a segment and along the anteroposterior axis. Axial patterning is controlled by homeotic genes of the Bithorax Complex (BXC) which are regionally expressed within the cardiac tube in non-overlapping domains. Ultrabithorax (Ubx) is expressed in the aorta whereas abdominal A (abd-A) is expressed in the heart, with the exception of the four most posterior cardiac cells which express Abdominal B (Abd-B). Ubx and abd-A functions are required to confer an aorta or a heart identity on cardiomyocytes, respectively. The anterior limit of the expression domain of Ubx, abd-A and Abd-B is independent of the function of the other genes. In contrast, abd-A represses Ubx expression in the heart and ectopic overexpression of abd-A transforms aorta cells into heart cardiomyocytes. Taken together, these results support the idea that BXC homeotic genes in the cardiac tube conform to the posterior prevalence rule.The cardiac tube is also segmentally patterned and each metamere contains six pairs of cardioblasts that are genetically diverse. We show that the transcription of seven up (svp), which is expressed in the two most posterior pairs of cardioblasts in each segment, is dependent on hedgehog (hh) signaling from the dorsal ectoderm. In combination with the axial information furnished by abd-A, the segmental hh-dependent information leads to the differentiation of the six pairs of svp-expressing cells into functional ostiae.Movies available on-line
AnFgf8mouse mutant phenocopies human 22q11 deletion syndrome
Authors: Frank Deborah U. , Fotheringham Lori K. , Brewer Judson A. , Muglia Louis J. , Tristani-Firouzi Martin , Capecchi Mario R. , Moon Anne M. 
Published: April 2021

Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear.Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest.The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.