bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of a rapid ultrasonographic technique for the evaluation of the abdominal organs in rabbits
Authors: Band Sarah A.
Published: June 2024

Background

Focused ultrasonographic imaging techniques are commonly used for cats and dogs; however, such techniques have not been described in rabbits.

Methods

Focused abdominal ultrasonography was performed on 12 healthy conscious rabbits using four acoustic windows: xiphisternal, left and right renal and cystic. They were positioned in sternal recumbency on a table top, with a cut‐out area to allow access to the ventral abdomen. Ultrasonographic images were obtained using a micro‐convex probe (3‒11 MHz), and the organs identified in each image were recorded.

Results

The liver, kidneys, stomach, duodenum, jejunum, caecum and colon were identified in all rabbits (12/12). In most rabbits, the following were identified: urinary bladder (11/12), gall bladder (11/12), spleen (10/12) and caudal vena cava or aorta (7/10). The right adrenal gland was identified in five of the 12 rabbits, but the left adrenal gland was identified in only one. The stomach filled at least one view in all rabbits, and the caecum filled the view in nine of 12 rabbits. Other structures thought to be identified included caecal flexures (9/12), appendix (9/12), ampulla coli (3/12), sacculus rotundus (3/12), colonic haustrae (2/12) and pancreas (2/12).

Limitation

Only neutered individuals were imaged, so the usefulness of the technique for imaging the reproductive organs could not be determined.

Conclusion

This technique enabled imaging of the major abdominal organs in most rabbits, demonstrating the potential value of focused imaging in this species.
Synthesis of silver‐doped TiO2 nanoparticles with highly efficient adsorption of Congo red
Authors: Nga Nguyen Kim , Mai Nguyen Thi Tuyet
Published: June 2024

TiO2 nanoparticles (NPs) doped with Ag were produced through a solvothermal method, with varying amounts of silver doping ranging from 0.5% to 1.5%. The samples were analyzed for crystallite sizes, structure, and metallic bondings using XRD, SEM, EDXS, and FTIR techniques. The BET surface areas were determined through nitrogen adsorption isotherms. The efficiency of the silver‐doped TiO2 NPs for removing Congo red (CR) was tested through adsorption experiments. The results showed that the synthesized TiO2 NPs doped with Ag were uniformly spherical in shape, with tiny average sizes ranging from 7.97 to 12.74 nm and large BET surface areas (98.41–166.1 m2 g−1). The silver‐doped TiO2 samples with a 0.5% Ag doping amount exhibited the highest adsorption capacity in CR removal, with a maximum adsorption capacity of 454.55 mg of dye per gram of adsorbent and a lower contact time of 20 min than other metal oxide NPs. The CR adsorption onto 0.5% Ag‐TiO2 obeyed the Langmuir isotherm model (R2 = 0.989), and the adsorption followed a pseudo‐second‐order kinetic equation. The adsorbent could be efficiently reused for five consecutive cycles to remove CR.
Profiling several key milk miRNAs and analysing their signalling pathways in dairy sheep breeds during peak and late lactation
Authors: Duman Esra , Özmen Özge , Kul Selim
Published: June 2024

Background

The comprehensive understanding of microRNAs (miRNAs) in sheep milk during various lactation periods and their impact on milk yield and composition remains limited.

Objectives

This study aimed to investigate the expression patterns of four highly expressed miRNAs in sheep milk and their association with milk composition and yield parameters during peak and late lactation stages.

Methods

A total of 40 healthy 4‐year‐old Akkaraman (n = 20) and Awassi (n = 20) ewes registered with the Ministry of Agriculture and Forestry of the Republic of Türkiye were used in the present study. For miRNA isolation from milk, the Qiagen miRNeasy Serum/Plasma Advanced Kit was utilised following the manufacturer's instructions. The expression levels of miRNAs were assessed using Qiagen miRNA PCR Assays.

Results

The significant fold changes in the expression levels of oar‐miR‐30a‐5p, oar‐miR‐148a and oar‐miR‐181a were observed between peak and late lactation periods in the Awassi sheep breed. Conversely, only oar‐miR‐30a‐5p and oar‐miR‐148a exhibited statistically significant changes in the Akkaraman sheep breed during the same lactation periods. Furthermore, oar‐miR‐21‐5p demonstrated a significant fold change exclusively in peak lactation compared to Akkaraman and Awassi ewes.

Conclusions

The findings suggest that the expression of the analysed miRNAs is influenced by both the lactation stage and different sheep breeds. This study offers valuable insights into the relationship between key miRNA expressions in sheep milk and milk composition and yield parameters during peak and late lactation, contributing to the existing knowledge in this field.
Prominent hair follicle epithelial mucinosis in a cat with eosinophilic plaque
Authors: Topcu Mehmet Emre , Yıldırım Funda
Published: June 2024

The feline eosinophilic granuloma complex is a well‐known dermatological problem that affects domestic cats. It has three characteristic components: eosinophilic plaque, eosinophilic granuloma and indolent ulcer. In this case report, we report a 5‐year‐old, mixed‐breed cat with pruritic plaque formation, which was typical for eosinophilic plaque by dermatological examination. The diagnosis was established by histopathological and clinical findings. As previous literature showed, hair follicle epithelium mucinosis as a histopathological finding could potentially give us fundamental clues about the microscopic diagnosis of this complex. We discuss the presentation, histopathology and treatment response in detail. This case highlights how intricate feline eosinophilic granuloma complex can be, and underscores the significance of hair follicle epithelium mucinosis as a diagnostic tool in histopathology.
Ultrasound‐guided percutaneous choledochocentesis in a cat with cholelithiasis, choledocholithiasis and cholangitis due to Klebsiella pneumoniae
Authors: Malliagros Larissa Vahia , Mendes Camila de Oliveira Ferreira , dos Santos Ayla Cerqueira Aleluia , Teixeira André Luis de Souza , Santos Márcia Carolina Salomão
Published: June 2024

A 13‐year‐old female cat was presented at our Veterinary Teaching Hospital with hyporexia and prostration. The animal underwent cholecystectomy 2 months previously due to partial biliary obstruction resulting from cholecystitis, multiple cholelithiasis, choledocholithiasis, dilation and tortuosity of the bile ducts. Due to the impossibility of puncturing the gall bladder and the persistence of dilation and tortuosity of the extra‐ and intrahepatic ducts identified by ultrasound, a dilated intrabiliary duct was punctured. The objective of the present study was to report the ultrasound‐guided percutaneous choledochocentesis technique, which, to our knowledge, is the first report of its performance in cats. The material was obtained for bile culture and antibiogram, which identified the bacterium Klebsiella pneumoniae, which was multiresistant to most antibiotics and uncommon in the biliary system. The technique was performed uneventfully, and was essential in the present report to assist in the presumptive diagnosis and treatment of cholangitis associated with cholelithiasis and choledocholithiasis.
Presumed intracranial and spinal subdural empyema secondary to periorbital abscesses in a golden retriever
Authors: Thong Patricia , Wolfenden Guy , Badsha Dazlyn , Lenard Zoe
Published: June 2024

Intracranial and spinal subdural empyema was presumptively diagnosed in a 2‐year‐old golden retriever secondary to periorbital abscesses. The patient initially presented to the referring veterinarian for right eye conjunctivitis, intermittent left head turn and reluctance to eat on the left side. The patient then suffered neck trauma from a rope, developing neck pain, left‐sided conscious proprioceptive deficits and right‐sided Horner's syndrome. Most signs resolved with medical management at the referring veterinarian, but neck pain persisted. Severe acute neurological deterioration occurred before presentation at our hospital, culminating in decerebrate rigidity and opisthotonos. Neurological exam revealed multifocal intracranial disease. Magnetic resonance imaging showed periorbital abscesses and extensive intracranial and cervical spinal subdural empyema. The owners elected for euthanasia and declined postmortem examination. Cerebrospinal fluid sampled immediately postmortem confirmed empyema. This is the first report of a presumed case of intracranial and cervical spine subdural empyema caused by periorbital abscesses in a dog.
Introduction
Authors: McIvor Charlotte , Walsh Ian R.
Published: June 2024

This Introduction outlines the structure of the book as it surveys contemporary Irish theatre from 1957 to the present in a two-part structure. Part I: Histories, situates the theatrical activity of twentieth- and twenty-first-century Ireland within its social and political contexts, identifies key practitioners, landmark productions, institutions, festivals and seminal revivals. Part II: Theories, offers five key theoretical frameworks—nation, language, body, space and interculturalism—to examine contemporary Irish theatre practices in the Republic and Northern Ireland. The deliberate decentralising of the play text and playwright as the most important nodal points for understanding the progression of contemporary Irish theatre is argued and the decision to foreground the contributions of artistic directors, scenographers, actors, directors, activists and administrators justified.
Conclusion
Authors: McIvor Charlotte , Walsh Ian R.
Published: June 2024

The authors here attempt to underpin the logic followed in their construction of a landscape of contemporary Irish theatre. Acknowledging how they built on the feminist counter-canonical interventions of the last 20 years the authors tease out how this publication is for them a feminist text. They know the book cannot be read exclusively as a feminist text, or as one type of feminist text but feel as a cisgender female and male writing team it is important politically, pedagogically and methodologically to claim the subtle refrain of the feminist text that guided the criteria for inclusion and discussion in terms of overall balance of representation across theatre case studies. They end by inviting readers to take this project forward to its next iteration.
Rapid Change, Revision and the “Troubles” (1966–1980)
Authors: McIvor Charlotte , Walsh Ian R.
Published: June 2024

The late 1960s and 1970s saw Ireland’s acceptance into the European Economic Community in 1973, educational reform, revisionist histories, increased urbanisation and the outbreak of sectarian violence in Northern Ireland, all of which prompted a break with previous convictions and ideologies. This chapter shows how theatrical activity reflected this change in its themes and practices with a new generation of directors and designers. An emphasis on regionalism led to the establishment of the Irish Touring Company and the founding of Druid in Galway. There were political experimentations in form, dramas critical of Catholic morality and plays that confronted the violence in the North. The Abbey produced seminal Beckett revivals, while productions at the Project Arts Centre brought the underrepresented urban working class to the fore.
The Celtic Tiger, Inward-Migration and the Peace Process (1994–2008)
Authors: McIvor Charlotte , Walsh Ian R.
Published: June 2024

The mid-1990s-late 2000s saw an explosion of fragmentation and experimentation in theatrical form with the economic transformation of Ireland during this Celtic Tiger period of financial growth, low unemployment and drastically improved Debt/GDP ratio. Unprecedented inward-migration and the establishment of a peace process in Northern Ireland allowed a greater diversity of theatrical work to be created and circulated globally. The dramatic text was decentralised with movement, dance and scenography increasingly taking centre stage and site-specific and/or site-responsive work developed. But the figure of the Irish playwright as globalised phenomenon and key reference point for Irish theatre was also rejuvenated through key successes while Druid Theatre Company revitalised the legacy of J. M. Synge as an early twentieth-century Irish master with their globally successful phenomenon DruidSynge.
Searching for Metaphors: Exploring Teacher Candidates’ Epistemological Frames
Authors: Hughes Richard , Brown Sarah Drake
Published: June 2024

Hughes and Drake Brown consider history teacher candidates’ conceptualization of the relationship among historians, history teachers, and history students, and they investigate the ways that teacher candidates’ understandings are manifested in their work in classrooms. Drawing from qualitative research on fifteen teacher candidates in the United States and the artifacts participants choose to represent their teaching identity, the authors argue that a significant break exists between teacher candidates’ understanding of the discipline of history, their articulated purposes as teachers, and the work that they perform with students during clinical experiences. The study underscores the importance of understanding not just the epistemology of emerging teachers, but also the complex relationship between their developing knowledge and actual classroom instruction.
Epistemological Issues in Teaching Global History
Authors: Gauthier-Trépanier Antoine
Published: June 2024

In this chapter, the author proposes to address some epistemological issues involved in teaching world history at the college level in Quebec, Canada. Indeed, because of the diversity that now characterizes history classes, but also the globalization of the issues that define our world today, it seems increasingly necessary to approach history from a global perspective. However, this perspective implies a reassessment of the aims associated with the teaching of history, which in Quebec is primarily thought of in a national context inscribed in the heritage of Western civilization. Thus, it raises numerous questions. Among them, what kind of global history is at stake, and how will teachers have to modify their relation to knowledge to adapt to the new program?
Why Does Epistemology Matter? A Personal Journey
Authors: Maggioni Liliana
Published: June 2024

The chapter addresses the development of epistemic cognition in history by merging the perspectives afforded by developmental studies of epistemic cognition and consciousness with the insights gained from the literature exploring the development of historical understanding and epistemically charged ideas such as evidence and historical accounts. Given the results obtained by studies attempting to assessing individual epistemic beliefs in history and teacher and student capacity to think historically, Maggioni proposes to interpret the instances of epistemic inconsistency and the challenges and limitations in developing the capacity to think historically that have been observed in light of the developmental psychology literature, and in particular of Kegan’s model of epistemic development. The chapter includes the identification of specific ideas and habits of mind that may act as stumbling blocks in the development of epistemic cognition in history and suggestions for pedagogical practice.
Elementary School Teachers’ Perspectives on History, 1920–1946
Authors: Samuelsson Johan
Published: June 2024

In this chapter Samuelsson looks at types of epistemic perspectives of history taught in Swedish elementary schools in 1920–1946. The material used consists of a large collection of 600 teachers’ descriptive accounts of teaching, as collected in 1946. The material provides a unique insight into teaching in the period, in part granting new perspectives on teaching. Even if the teachers had an objectivist perspective on history, Samuelsson argues that they also used a more constructivist perspective: Pupils worked with statistical yearbooks, collected historical artefacts and worked independently on various tasks. Samuelsson then relates these results to, among others, Klafki’s theory on teaching.
Mapping Teachers’ Epistemic Beliefs in Collegial Planning
Authors: Nordgren Kenneth
Published: June 2024

Nordgren explores a complementary path to teachers’ epistemic cognition that goes beyond the predominant focus on individual thinking. Based on a longitudinal project that follows teachers engaged in planning in subject-based teams, this chapter focuses on how teachers’ epistemic beliefs evolve in the act of pedagogical recontextualization. Methodologically, the collegial setting allows real-time access to teachers’ negotiations and decisions about content, learning goals, sequencing, and adjustments to students’ needs, without the filters of questionnaires and interviews. Theoretically, the findings problematize the analytical use of categorical epistemic stances and the separation of epistemic from non-epistemic objectives within teachers’ epistemic beliefs. Nordgren thus shows how history teachers’ planning takes place within an intricate web of epistemic choices regarding ontological assumptions, classroom management, and almost everything in between.
Going Beyond the Scoring Grid: How the Topic of Assessment Can Promote Reflection on Epistemic Beliefs and Agency in History Education
Authors: Duquette Catherine , Brunet Marie-Hélène , Dufour Arianne , Lille Benjamin
Published: June 2024

An overarching aim of professional development for teachers in history education is to foster a more complex understanding of the discipline. Yet, substantial research underlines the stability of history teachers’ epistemological beliefs, demonstrating the difficulties they experience in shifting from their existing positivist approach to a more critical mindset. Could some contexts be more favorable to enhancing epistemic agency through in-depth reflection? This chapter discusses the potential of examining assessment as a method of encouraging teachers to question their epistemological understanding of history. Based on the results of a study conducted with six Quebec teachers, it illustrates how questioning assessment practices in a collaborative approach creates a space favorable to epistemological wobbling.
JT gravity from non-Abelian T-duality
Authors: Bielli Daniele , Penati Silvia , Ramirez Anayeli
Published: June 2024

Abstract

We study the geometries obtained by performing super non-Abelian T-duality of the Principal Chiral Model on OSp(1|2). While the initial model represents an appropriate 3D supergravity background, interpretable as the superspace version of AdS3, the T-dual model fails solving the 3D supergravity torsion constraints. We argue that this has to do with a factorisation pattern taking place under dualisation: the dual 3D geometry can be rewritten as the supersymmetric version of AdS2, satisfying the supergravity constraints, fibered over what we interpret as the superspace equivalent of the standard bosonic line. We discuss an interesting connection between T-duals of generic Principal Chiral Models and Poisson sigma models. We exploit it to show that in a suitable limit the dual action studied in this work gives rise to JT (super)gravity.
Entanglement harvesting in cosmic string spacetime
Authors: Ji Ying , Zhang Jialin , Yu Hongwei
Published: June 2024

Abstract

We investigate the entanglement harvesting phenomenon for static detectors that locally interact with massless scalar fields in the cosmic string spacetime, which, though locally flat, features a conical structure defined by a deficit angle. Specifically, we analyze three detector alignments relative to the string: parallel and orthogonal alignments with detectors on the same side of the string, and an orthogonal alignment with detectors on opposite sides of the string. For the alignments on the same side of the string, we observe that the cosmic string’s presence can either aid or hinder entanglement harvesting, affecting both the extent of entanglement harvested and the achievable range of interdetector separation. This effect depends on the distance between the detectors and the string and differs markedly from scenarios in a locally flat spacetime with a reflecting boundary, where the boundary invariably extends the harvesting-achievable range. Conversely, for the alignment with detectors on opposite sides of the string, we find that detectors consistently harvest more entanglement than those in a flat spacetime devoid of a cosmic string. This starkly contrasts the behavior observed with detectors on the same side. Interestingly, the presence of a cosmic string expands the harvesting-achievable range for detectors in orthogonal alignment only when near the string, whereas it invariably reduces the achievable range for detectors in parallel alignment.
Higher-derivative deformations of the ModMax theory
Authors: Kuzenko Sergei M. , Raptakis Emmanouil S. N.
Published: June 2024

Abstract

We present higher-derivative deformations of the ModMax theory which preserve both U(1) duality symmetry and Weyl invariance. In particular, we single out a class of deformations expected to describe a low-energy effective action for the ModMax theory. We also elaborate on (higher-derivative) deformations of the $$ \mathcal{N} $$
N
= 1 super ModMax theory.
Probing the mixing between sterile and tau neutrinos in the SHiP experiment
Authors: Choi Ki-Young , Kim Sung Hyun , Kim Yeong Gyun , Lee Kang Young , Lee Kyong Sei , Do Park Byung , Sohn Jong Yoon , Yoo Seong Moon , Yoon Chun Sil
Published: June 2024

Abstract

We study the expected sensitivity to the mixing between sterile and tau neutrinos directly from the tau neutrino disappearance in the high-energy fixed target experiment. Here, the beam energy is large enough to produce tau neutrinos at the target with large luminosity. During their propagation to the detector, tau neutrinos may oscillate into sterile neutrinos. By examining the energy spectrum of the observed tau neutrino events, we can probe the mixing between sterile and tau neutrinos directly. In this paper, we consider Scattering and Neutrino Detector (SND) at SHiP experiment as a showcase, which uses 400 GeV protons from SPS at CERN, and expect to observe 7,300 tau and anti-tau neutrinos from the 2 × 1020 POT for 5 years operation. Assuming the uncertainty of 10%, we find the sensitivity |Uτ4|2 ∼ 0.08 (90% CL) for $$ \Delta {m}_{41}^2 $$
∆

m
41
2

∼ 500 eV2 with 10% background to the signal. We also consider a far SND at the end of the SHiP Hidden Sector Decay Spectrometer (HSDS), in which case the sensitivity would be enhanced to |Uτ4|2 ∼ 0.02. Away from this mass, the sensitivity becomes lower than |Uτ4|2 ∼ 0.15 for $$ \Delta {m}_{41}^2 $$
∆

m
41
2

≲ 100 eV2 or $$ \Delta {m}_{41}^2 $$
∆

m
41
2

≳ 104eV2.
INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death
Authors: Labat-de-Hoz Leticia , Fernández-Martín Laura , Correas Isabel , Alonso Miguel A.
Published: June 2024

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)—a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.
Low Tropospheric Wind Forecasts in Aviation: The Potential of Deep Learning for Terminal Aerodrome Forecast Bulletins
Authors: Alves Décio , Mendonça Fábio , Mostafa Sheikh Shanawaz , Morgado-Dias Fernando
Published: June 2024

In aviation, accurate wind prediction is crucial, especially during takeoff and landing at complex sites like Gran Canaria Airport. This study evaluated five Deep Learning models: Long Short-Term Memory (LSTM), Vanilla Recurrent Neural Network (vRNN), One-Dimensional Convolutional Neural Network (1dCNN), Convolutional Neural Network Long Short-Term Memory (CNN-LSTM), and Gated Recurrent Unit (GRU) for forecasting wind speed and direction. The LSTM model demonstrated the highest precision, particularly for extended forecasting periods, achieving a mean absolute error (MAE) of 1.23 m/s and a circular MAE (cMAE) of 15.80° for wind speed and direction, respectively, aligning with World Meteorological Organization standards for Terminal Aerodrome Forecasts (TAF). While the GRU and CNN-LSTM also showed promising results, and the 1dCNN excelled in wind direction forecasting over shorter intervals, the vRNN lagged in performance. Additionally, the autoregressive integrated moving average model underperformed relative to the DL models, underscoring the potential of DL, particularly LSTM, in enhancing TAF accuracy at airports with intricate wind patterns. This study not only confirms the superiority of DL over traditional methods but also highlights the promise of integrating artificial intelligence into TAF automation.
The role of job strain in the relationship between depression and long-term sickness absence: a register-based cohort study
Authors: Jarroch Rand , Falkstedt Daniel , Nevriana Alicia , Pan Kuan-Yu , Kauhanen Jussi , Almroth Melody
Published: June 2024

Purpose

Though individuals with depression and those with poor working conditions are more likely to be on long-term sickness absence (LTSA), less is known about how working conditions may modify the associations between depression status and LTSA. This study aims to examine the association between depression and LTSA among Swedish workers with different levels of job strain and its individual components (job demands and job control).

Methods

All Swedish workers 30 − 60 years old (N = 3,065,258) were studied in 2005. At baseline (2005–2010), workers were categorized as: without depression, being prescribed antidepressants, and being in inpatient/outpatient care. Job strain was measured using a Swedish Job Exposure Matrix, and data on LTSA were obtained from 2011 to 2021. The association between depression and LTSA was assessed using Cox proportional-hazards regression stratified by categories of job strain.

Results

Compared to workers without depression, workers with depression had higher risk of LTSA across all job strain levels. Depression was associated with the highest hazards of LTSA in active jobs, but a similar population attributable fraction (PAF) was found across categories of job strain, indicating similarities between the different categories.

Conclusion

There was evidence of a moderating effect of job strain in the relationship between depression and LTSA, but also evidence that this was due to differences in baseline depression prevalence in the different job strain categories. Future research is needed to determine alternative factors which could be relevant for reducing LTSA among those who have already developed depression.
Simultaneous multi-targeted forensic toxicological screening in biological matrices by MRM-IDA-EPI mode
Authors: Franzin Martina , Di Lenardo Rebecca , Ruoso Rachele , Dossetto Paolo , D’Errico Stefano , Addobbati Riccardo
Published: June 2024

The toxicologist ascertains drug assumptions in case of paediatric intoxications and death for overdose. The analytical approach consists of initially screening and consequently confirming drug positivity. We developed a toxicological screening method and validated its use comparing the results with a LC–MS/MS analysis. The method identifies 751 drugs and metabolites (704 in positive and 47 in negative mode). Chromatographic separation was achieved eluting mobile phase A (10 mM ammonium formate) and B (0.05% formic acid in methanol) in gradient on Kinetex Phenyl-Hexyl (50 × 4.6 mm, 2.6 μm) with 0.7 mL/min flow rate for 11 min. Multiple Reaction Monitoring (MRM) was adopted as survey scan and, after an Information-Dependent Analysis (IDA) (threshold of 30,000 for positive and 1000 cps for negative mode), the Enhanced Product Ion (scan range: 50–700 amu) was triggered. The MS/MS spectrum generated was compared with one of the libraries for identification. Data processing was optimised through creation of rules. Sample preparation, mainly consisting of deproteinization and enzymatic hydrolysis, was set up for different matrices (blood, urine, vitreous humor, synovial fluid, cadaveric tissues and larvae). Cut-off for most analytes resulted in the lowest concentration tested. When the results from the screening and LC–MS/MS analysis were compared, an optimal percentage of agreement (100%) was assessed for all matrices. Method applicability was evaluated on real paediatric intoxications and forensic cases. In conclusion, we proposed a multi-targeted, fast, sensitive and specific MRM-IDA-EPI screening having an extensive use in different toxicological fields.
Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia
Authors: Karabay Arzu Zeynep , Ozkan Tulin , Karadag Gurel Aynur , Koc Asli , Hekmatshoar Yalda , Sunguroglu Asuman , Aktan Fugen , Buyukbingöl Zeliha
Published: June 2024

Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.

Graphical Abstract
Analysis of clinical studies on clozapine from 2012-2022
Authors: Freibüchler Anton , Seifert Roland
Published: June 2024

Clozapine has been considered the “gold standard” in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of negative symptoms and suicidal behaviour. However, due to its numerous adverse reactions, clozapine is mainly used for treatment-resistant schizophrenia. The aim of this paper is to analyze the results of clinical studies on clozapine from 2012-2022. PubMed was used as the database. Sixty-four studies were included and categorised by topic. The pharmacokinetic properties of clozapine tablets and a clozapine suspension solution did not differ markedly. Clozapine was superior to olanzapine and risperidone in reducing aggression and depression. A long-term study showed that metabolic parameters changed comparably with olanzapine and clozapine after 8 years. Risperidone and ziprasidone can be used as an alternative to clozapine. Scopolamine, atropine drops, and metoclopramide are effective in the treatment of clozapine-induced hypersalivation. Eight drugs, including liraglutide, exenatide, metformin, and orlistat, are potentially effective in the treatment of clozapine-induced weight gain. Ziprasidone, haloperidol, and aripiprazole showed a positive effect on symptoms when added to clozapine. No investigated drug was superior to clozapine for the treatment of schizophrenia. Ziprasidone and risperidone can also be used well for the treatment of schizophrenia. In the treatment of clozapine-induced hypersalivation and weight gain, some drugs proved to be effective.
A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants
Authors: Kuemmerle Andrea , Gossen Denis , Marx Michael W. , Lorch Ulrike , Szramowska Maja , Kumar Ashok , Singh Dharmendra , Singh Satinder , Ramachandruni Hanu , Thankachen Byju , Kore Swapnil , Gaaloul Myriam El , Borghini-Fuhrer Isabelle , Chalon Stephan
Published: June 2024

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18–55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021)
Short-term adaptation as a tool to improve bioethanol production using grass press-juice as fermentation medium
Authors: Varriale Ludovica , Geib Doris , Ulber Roland
Published: June 2024

Grass raw materials collected from grasslands cover more than 30% of Europe’s agricultural area. They are considered very attractive for the production of different biochemicals and biofuels due to their high availability and renewability. In this study, a perennial ryegrass (Lolium perenne) was exploited for second-generation bioethanol production. Grass press–cake and grass press-juice were separated using mechanical pretreatment, and the obtained juice was used as a fermentation medium. In this work, Saccharomyces cerevisiae was utilized for bioethanol production using the grass press-juice as the sole fermentation medium. The yeast was able to release about 11 g/L of ethanol in 72 h, with a total production yield of 0.38 ± 0.2 gEthanol/gsugars. It was assessed to improve the fermentation ability of Saccharomyces cerevisiae by using the short-term adaptation. For this purpose, the yeast was initially propagated in increasing the concentration of press-juice. Then, the yeast cells were re-cultivated in 100%(v/v) fresh juice to verify if it had improved the fermentation efficiency. The fructose conversion increased from 79 to 90%, and the ethanol titers reached 18 g/L resulting in a final yield of 0.50 ± 0.06 gEthanol/gsugars with a volumetric productivity of 0.44 ± 0.00 g/Lh. The overall results proved that short-term adaptation was successfully used to improve bioethanol production with S. cerevisiae using grass press-juice as fermentation medium.

Key points

• Mechanical pretreatment of grass raw materials

• Production of bioethanol using grass press-juice as fermentation medium

• Short-term adaptation as a tool to improve the bioethanol production
Biocalorimetry-aided monitoring of fungal pretreatment of lignocellulosic agricultural residues
Authors: Duong Hieu Linh , Paufler Sven , Harms Hauke , Maskow Thomas , Schlosser Dietmar
Published: June 2024

The present study aimed to investigate whether and how non-invasive biocalorimetric measurements could serve for process monitoring of fungal pretreatment during solid-state fermentation (SSF) of lignocellulosic agricultural residues such as wheat straw. Seven filamentous fungi representing different lignocellulose decay types were employed. Water-soluble sugars being immediately available after fungal pretreatment and those becoming water-extractable after enzymatic digestion of pretreated wheat straw with hydrolysing (hemi)cellulases were considered to constitute the total bioaccessible sugar fraction. The latter was used to indicate the success of pretreatments and linked to corresponding species-specific metabolic heat yield coefficients (YQ/X) derived from metabolic heat flux measurements during fungal wheat straw colonisation. An YQ/X range of about 120 to 140 kJ/g was seemingly optimal for pretreatment upon consideration of all investigated fungi and application of a non-linear Gaussian fitting model. Upon exclusion from analysis of the brown-rot basidiomycete Gloeophyllum trabeum, which differs from all other here investigated fungi in employing extracellular Fenton chemistry for lignocellulose decomposition, a linear relationship where amounts of total bioaccessible sugars were suggested to increase with increasing YQ/X values was obtained. It remains to be elucidated whether an YQ/X range being optimal for fungal pretreatment could firmly be established, or if the sugar accessibility for post-treatment generally increases with increasing YQ/X values as long as “conventional” enzymatic, i.e. (hemi)cellulase-based, lignocellulose decomposition mechanisms are operative. In any case, metabolic heat measurement–derived parameters such as YQ/X values may become very valuable tools supporting the assessment of the suitability of different fungal species for pretreatment of lignocellulosic substrates.

Key points

• Biocalorimetry was used to monitor wheat straw pretreatment with seven filamentous fungi.

• Metabolic heat yield coefficients (YQ/X) seem to indicate pretreatment success.

• YQ/X values may support the selection of suitable fungal strains for pretreatment.
Ruxolitinib for the treatment of acute graft-versus-host disease: a retrospective analysis
Authors: Denk Alexander , Edinger Matthias , Weber Daniela , Holler Ernst , Fante Matthias , Meedt Elisabeth , Gunes Sibel , Poeck Hendrik , Mittermaier Cornelia , Herr Wolfgang , Wolff Daniel
Published: June 2024

Steroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7–21) after aGvHD onset; median duration of administration was 37 days (range, 20–86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95–905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib.
Efficacy and safety of ruxolitinib in the treatment of chronic graft-versus-host disease: a retrospective analysis
Authors: Denk Alexander , Mittermaier Cornelia , Weber Daniela , Fante Matthias , Güneş Sibel , Edinger Matthias , Herr Wolfgang , Wolff Daniel
Published: June 2024

Steroid-refractory chronic graft-versus-host disease (cGvHD) is associated with significant morbidity and mortality, with ruxolitinib being the first drug approved for its treatment. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of cGvHD at our center between 07/2015 and 12/2022 and identified 48 patients receiving ruxolitinib as second (18/48) or advanced (30/48) treatment line. Ruxolitinib was started on median day 340 (range 119–595) after cGvHD onset; median duration of administration was 176 (range, 79–294) days with 16/48 patients continuing treatment at last follow-up. National Institutes of Health organ grading and the intensity of immunosuppression were assessed at the start of ruxolitinib treatment and repeated after 1, 3, 6, and 12 months. Response assessment was terminated at the start of any additional new immunosuppressant treatment. The median time of follow-up was 582 (range, 104–1161) days. At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%. Infectious adverse events ≥ CTCAE grade III were observed in 10/48 patients. The response rate was not associated with the severity of cGvHD, number of previous treatment lines, or number of additional agents combined with ruxolitinib applying a univariate regression model. At the time of the 12-month follow-up, four patients experienced recurrence of the underlying malignancy and two patients had experienced non-relapse-related mortality. Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population.
In distributive phosphorylation catalytic constants enable non-trivial dynamics
Authors: Conradi Carsten , Mincheva Maya
Published: June 2024

Ordered distributive double phosphorylation is a recurrent motif in intracellular signaling and control. It is either sequential (where the site phosphorylated last is dephosphorylated first) or cyclic (where the site phosphorylated first is dephosphorylated first). Sequential distributive double phosphorylation has been extensively studied and an inequality involving only the catalytic constants of kinase and phosphatase is known to be sufficient for multistationarity. As multistationarity is necessary for bistability it has been argued that these constants enable bistability. Here we show for cyclic distributive double phosphorylation that if its catalytic constants satisfy an analogous inequality, then Hopf bifurcations and hence sustained oscillations can occur. Hence we argue that in distributive double phosphorylation (sequential or distributive) the catalytic constants enable non-trivial dynamics. In fact, if the rate constant values in a network of cyclic distributive double phosphorylation satisfy this inequality, then a network of sequential distributive double phosphorylation with the same rate constant values will show multistationarity—albeit for different values of the total concentrations. For cyclic distributive double phosphorylation we further describe a procedure to generate rate constant values where Hopf bifurcations and hence sustained oscillations can occur. This may, for example, allow for an efficient sampling of oscillatory regions in parameter space. Our analysis is greatly simplified by the fact that it is possible to reduce the network of cyclic distributive double phosphorylation to what we call a network with a single extreme ray. We summarize key properties of these networks.
Is there a connection between spine alignment, chest mobility, shoulder joint and respiratory parameters of patients with ankylosing spondylitis?
Authors: Szewczyk Daniel , Sadura-Sieklucka Teresa , Tarnacka Beata , Sokołowska Beata
Published: June 2024

Introduction

Ankylosing spondylitis is chronic progressive disease, which decrease functions of musculoskeletal system including chest area. Those changes influences respiratory mechanics, worsen conditions of proper ventilation of lungs.

Objectives

Rating of functional and respiratory parameters and dependence between them at patients with ankylosing spondylitis.

Materials & methods

The study included 45 patients with diagnosed ankylosing spondylitis. Chest and upper limbs mobility, resting spinal curvature alignment were assessed, and respiratory parameters were measured in a plethysmographic chamber JAGGER MasterScreen Body.

Results

Ankylosing spondylitis patients had lower respiratory parameters especially sReff, and FRC. Restriction of chest and upper limbs mobility was also demonstrated. Forward head extension was observed based on the occipital wall test. Correlations between functional parameters and correlations between functional and respiratory parameters were shown, in particular MIP, MEP, sReff, Rtot, TLC, ERV.

Conclusions

The study confirmed a decrease in functional and respiratory parameters in the examined patients with ankylosing spondylitis compared to the applicable standards. A significant relationship was found between functional parameters in the upper body and respiratory parameters, which worsen with increasing thoracic dysfunction. The obtained results indicate the directions of therapy that should be taken into account to improve respiratory parameters and reduce respiratory dysfunction in these patients. Chest-focused physiotherapy appears to be an important element in improving function in patients with ankylosing spondylitis.