bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of heavy metals content in well water and its predictive insights for students' wellbeing in Almajiri Schools, Sokoto East, Nigeria
Authors: Sarkingobir Yusuf , Umar A.I. , Waheed Syed A. , Miya Yusuf Yahaya , Sahabi Mustapha , Salah Nura Maiakwai
Published: September 2023

Education is a right to every child, but Sokoto is suffering from many issues ravaging education, therewith, a major issue is the Almajiri school. Because the Almajiri schools are abandoned there is every tendency that their drinking water is contaminated considering the rising pattern of pollution across the globe. The aim of the study was to carry out an analysis of heavy metal content in well water and propel some predictive insights for students well-being in Almajiri schools in Sokoto, Nigeria.Â  Samples of well water were collected from Almajiri schools in Sokoto state and metals were analyzed using atomic abortion spectroscopy. 60.10 Â± 5.1 to 600.1Â± 0.01, 100.1 Â± 0.5 to 600.0 Â± 0.02, are the ranges of calcium, and magnesium macroelements determined.Â  The ranges for essential heavy metals zinc, and iron are as follows; 2.34 Â± 0.05 to 5.00 Â± 0.02 (zinc), and 0.54Â± 0.05 to 10.43 Â± 0.5 (iron) respectively. The ranges of Pb, Hg, and Cd assessed are as follows: lead (0.0 to 1.06 Â± 0.005), mercury (0.10 Â± 0.002 to 2.501 Â± 0.01), and cadmium (0.00122 Â±0.0004 to 0.0761 Â± 0.0001). The HI for the heavy metals determined are in the order of schools B>D>A>C. The metals determined are either excess or little (with respect to essential heavy metals) in many cases.Â  In one school, the HI is far above 1 and therefore risk the population with effects. Thus, can elicit harm to the consumers. They can affect the academic, cognitive capacity of the Alamjiri children. There is need to take proper measures to save the health and future development of the Almajiri child against heavy metals poisoning possibility.
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Reflections beyond implementation: Evaluation of the project-based learning in the research curriculum of the Philippine Science High School - Luzon campuses
Authors: Dacumos Leo Peter , Silva Dorothy
Published: September 2023

STEM schools have put priority on establishing research education as a core program that enables students to choose a topic of their choice, identify a problem, and find a solution to it through experimentation and other modes of data collection. At the Philippine Science High Schools, one of its key goals is to foster a research culture among its scholars, who will help to strengthen the country's academic and scientific workforce and contribute to its success in the future. To improve instructional teaching, the project-based learning (PBL) approach has been utilized in many academic courses. A cache of studies has delved into the use of project-based learning approaches in many academic courses but the research education. This research project aimed to evaluate the implementation of project-based learning (PBL) in the STEM Research curriculum of the Philippine Science High School â€“ Luzon campuses. Select teachers from the Philippine Science High School have shared their thoughts through the qualitative interview tool. The use of qualitative interview tool is aimed to explore their thoughts and opinions regarding the various aspects of project-based learning (PBL) implementation within the PSHS research curriculum. Thematic analysis using phenomenological reduction shows emerging themes highlighting the benefits, challenges, and things that are needed to start to improve the implementation of the project-based learning approach within the research curriculum of the PSHS system.
The Effect of Computational-Based Learning Media Using the STAD Type Cooperative Model on Student Learning Outcomes and Motivation on the Subject of Intermolecular Forces
Authors: Nababan Tiur Maida Br. , Pratiwi Ledy , Nugraha Asep Wahyu
Published: September 2023

This study aims to determine the effect of computational chemistry-based learning media using the STAD type cooperative learning model on student learning outcomes and motivation on the subject of forces between molecules. The population in this study were grade X students in high schools in Medan city which amounted to 7 classes. The samples of this study were students of class X IPA 3 and X IPA 5, each of which amounted to 36 students. The research instruments used were test instruments in the form of 20 multiple choice questions and non-test in the form of 30 statements. The quality of the research instrument was tested using validity, reliability, difficulty level of questions and differentiating power to determine the questions that would be used as instruments in the study. The data analysis technique shows that in the learning outcomes hypothesis test, the t-count> t-table value is 5.03>1.666 and the results of the learning motivation hypothesis test, the t-count> t-table value is 3.12>1.666. This data shows that there is an effect of computational chemistry-based learning media using the STAD type cooperative learning model on student learning outcomes and motivation on the subject of forces between molecules.
Radiofrequency ablation via an implanted self-expandable metallic stent to treat in-stent restenosis in a rat gastric outlet obstruction model
Authors: Won Dong-Sung , Park Yubeen , Zeng Chu Hui , Ryu Dae Sung , Kim Ji Won , Kang Jeon Min , Kim Song Hee , Kim Hyung-Sik , Lee Sang Soo , Park Jung-Hoon
Published: September 2023

Background: In-stent restenosis caused by tissue hyperplasia and tumor growth through the wire meshes of an implanted self-expandable metallic stent (SEMS) remains an unresolved obstacle. This study aimed to investigate the safety and efficacy of SEMS-mediated radiofrequency ablation (RFA) for treating stent-induced tissue hyperplasia in a rat gastric outlet obstruction model.

Methods: The ablation zone was investigated using extracted porcine liver according to the ablation time. The optimal RFA parameters were evaluated in the dissected rat gastric outlet. We allocated 40 male rats to four groups of 10 rats as follows: group A, SEMS placement only; group B, SEMS-mediated RFA at 4 weeks; group C, SEMS-mediated RFA at 4 weeks and housed until 8 weeks; and group D, SEMS-mediated RFA at 4 and 8 weeks. Endoscopy and fluoroscopy for in vivo imaging and histological and immunohistochemical analysis were performed to compare experimental groups.

Results: Stent placement and SEMS-mediated RFA with an optimized RFA parameter were technically successful in all groups. Granulation tissue formation-related variables were significantly higher in group A than in groups B–D (all p < 0.05). Endoscopic and histological findings confirmed that the degrees of stent-induced tissue hyperplasia in group D were significantly lower than in groups B and C (all p < 0.05). Hsp70 and TUNEL expressions were significantly higher in groups B–D than in group A (all p < 0.001).

Conclusion: The implanted SEMS-mediated RFA successfully managed stent-induced tissue hyperplasia, and repeated or periodic RFA seems to be more effective in treating in-stent restenosis in a rat gastric outlet obstruction model.
Perceptions of the crowded sky as assessed through response to aerial infrastructure
Authors: Kolbmann Christina L. , Leslie Carrie , Anderson Chris , Kelly Jeff F. , Ross Jeremy D. , Jervis Lori , Reedy Justin , Bridge Eli Samuel
Published: September 2023

Ever increasing numbers of wind turbines, communication towers, power lines, and aerial vehicles are clear evidence of our growing reliance on infrastructure in the lower aerosphere. As this infrastructure expands, it is important to understand public perceptions of an increasingly crowded sky. To gauge tolerance for aerial crowding, 251 participants from across the US completed a survey where they rated tolerance for a series of aerial infrastructure images (i.e., towers, turbines, and airborne vehicles) in four landscapes with varying degrees of pre-existing ground-level infrastructure that approximated rural, suburban, and urban settings. We predicted lower tolerance for aerial infrastructure 1) in more natural scenes and 2) among rural residents. In general, participants preferred an open aesthetic with relatively little aerial infrastructure across all landscape types. No clear association was found between infrastructure tolerance and natural scenes nor rural residency, with participants slightly less tolerant of infrastructure in the suburban scene. Tolerance scores were generally similar across age, income levels, and political affiliations. Women indicated less crowding tolerance than men, with this effect driven by a disproportionate number of women with zero tolerance for aerial infrastructure. African Americans and Asians had higher tolerance scores than other racial/ethnic groups, but these trends may have been affected by low sample sizes of non-white participants. Our survey revealed fewer differences in crowding tolerance across demographic groups than might be expected given widely reported political and geographic polarization in the U.S. Attitudes toward aerial infrastructure were varied with few associations with demographic parameters suggesting that public opinion has not yet solidified with regard to this issue, making possible opportunities for consensus building with regard to responsible development of aerial infrastructure.
Synthesis, in-vitro inhibition of cyclooxygenases and in silico studies of new isoxazole derivatives
Authors: Alam Waqas , Khan Haroon , Saeed Jan Muhammad , Rashid Umer , Abusharha Ali , Daglia Maria
Published: September 2023

Isoxazole belongs to the class of five-membered heterocyclic compounds. The process of developing new drugs has significantly gained attention due to inadequate pharmacokinetic and safety attributes of the available drugs. This study aimed to design a new diverse array of ten novel isoxazole derivatives via Claisen Schmidt condensation reaction. In vitro COX-1/2 anti-inflammatory assay, in silico molecular docking of potent compounds, Molecular docking simulation, and SwissADME pharmacokinetic profile were investigated in this research. The in vitro COX-1 and COX-2 enzyme inhibitory assay showed that almost all the tested compounds exhibited anti-inflammatory effects whereas C6, C5, and C3 were found to be the most potent COX-2 enzyme inhibitors among the tested compounds and are good candidates for selective COX-2 inhibitors. In silico molecular docking studies coupled with molecular dynamic simulation has been done to rationalize the time-evolved mode of interaction of selected inhibitor inside the active pockets of target COX-2. The binding orientations and binding energy results also showed the selectivity of compounds towards COX-2. Physicochemical properties, pharmacokinetic profile, lipophilicity, water solubility, drug metabolism, drug-likeness properties, and medicinal chemistry of the synthesized isoxazole derivatives were assessed. The SwissADME (absorption, distribution, metabolism, and excretion) database was used to assess the physicochemical properties and drug-likeness properties of the synthesized isoxazole derivatives. All the compounds were shown high GI absorption except Compound 7 (C7). Compound 1 (C1) and Compound 2 (C2) were found to cross the blood-brain barrier (BBB). Lipinski’s rule of five is not violated by any of the ten synthesized isoxazole derivatives. It was predicted with the SwissADME database that C2, C5, C6, C7, and C8 are potent inhibitors of cytochrome (CYP) subtype CYP-2C19. A subtype of CYP-2C9 was inhibited by C4 and C7. The medicinal chemistry of all the compounds C1-C10 showed no PAIN (Pan assay interference compounds) alerts. The improved gastrointestinal (GI) absorption and BBB permeability of C1 and C2 can provide a future prospective for new researchers in the medicinal field to investigate the compounds for the management of chronic diseases. The synthesized isoxazole compounds showed excellent in vitro COX-1/2 enzymes anti-inflammatory investigations, in silico studies, good physicochemical properties, and improved pharmacokinetic profile which will be further investigated via in vivo anti-inflammatory activities. Moreover, to further support our findings of the computational research and in vitro studies, an in-vivo pharmacokinetic profile is suggested in the future.
Navigating a transforming landscape: the evolving role of pharmacovigilance physicians in drug development and implications for future challenges and training requirements
Authors: Hammad Tarek A. , Afsar Salman , Le-Louet Herve , Kugener Veronique F.
Published: September 2023

Contrary to the famous quote from Voltaire, “The art of medicine consists in amusing the patient, while nature cures the disease”, medicine has evolved since the 17th century into a multi-faceted scientific field facilitating healing and improving overall wellbeing. One rapidly evolving area within this field is drug safety, also known as pharmacovigilance (PV). PV identifies and evaluates potential risks throughout the life cycle of the drug, minimizing patient exposure to harmful effects and guiding appropriate risk mitigation and management strategies. Timely identification and mitigation of risks not only contribute to patient safety but also allows maximum therapeutic benefits while curtailing economic burden associated with adverse events. In the evolving landscape of drug safety, the role of the PV physicians has emerged as an integral component of drug development. This paper aims to explore the evolving nature of PV physicians’ roles in drug development, highlighting changing landscape in drug development and safety monitoring and attendant changes and advancements in responsibilities, scope, and training implications. To be well-rounded, PV physicians are encouraged to strive to undergo relevant training and education. This would enable them to leverage pertinent complementary fields of science by developing the proficiency to ask the right questions, acknowledge multidisciplinary perspectives, and interpret the overall evidence. While on-the-job training is valuable for gaining experience, building a future safety workforce necessitates more targeted efforts, especially considering that medical school curricula may not readily emphasize the development of skills required for successful PV physician roles. Therefore, academic centers, pharmaceutical companies, and regulatory agencies should increase collaboration to establish hands-on training opportunities through post-doctoral, internship, and fellowship programs, in order to meet the growing demand for well-trained PV physicians.
First record of Oceanic Anoxic Event 2 in the Eastern Carpathians: implications for chemostratigraphic and biostratigraphic correlations
Authors: Melinte-Dobrinescu Mihaela , Ion Gabriel , Anton Eliza , Apotrosoaei Vlad , Briceag Andrei , Lazăr Constantin
Published: September 2023

This study aims to investigate a marlstone and claystone succession located at the southern end of the Eastern Carpathians, a region where oceanic anoxic event 2 (OAE2) has not been pointed out so far. Toward the upper half of this succession, a 17-cm-thick black shale was identified. The investigated depositional interval lies within the late Cenomanian–early Turonian, encompassing the UC3d up to UC7 nannofossil zones. The δ13C values fluctuated between 2.06‰ and 3.89‰, showing a positive isotope excursion that was assigned to OAE2. The δ13C isotope curve displays the following intervals: pre-excursion, first build-up, trough, second build-up, plateau, and post-excursion. Within the second build-up interval of OAE2, a substantial shift in CaCO3 values, accompanied by high concentrations of total organic carbon and a significant decline in the abundance and diversity of calcareous nannofossil assemblages, was observed. The nannofossil turnover related to OAE2 climax revealed predominance of Watznaueria barnesiae and temporary disappearance from the record of surface-water higher fertility taxa, such as Biscutum constans, Zeugrhabdotus erectus, and Discorhabdus ignotus. Above OAE2, peaks of Eprolithus floralis, followed by increased abundance of Eiffellithus turriseiffelii and Nannoconus spp., were identified. In the lower part of the studied succession (i.e., the upper Cenomanian UC3d nannofossil subzone), during the pre-excursion characterized by low δ13C values and less negative δ18O values, a small group of nannofossils more related to mid- and high-paleolatitudes, such as Crucibiscutum salebrosum, Repagulum parvidentatum, and Seribiscutum primitivum, is present, always showing a low abundance.
Case report: a premature infant with severe intrauterine growth restriction, adrenal insufficiency, and inflammatory diarrhea: a genetically confirmed case of MIRAGE syndrome
Authors: Go Anna , Lee Beom Hee , Choi Jin-Ho , Jeong Jiyoon , Jung Euiseok , Lee Byong Sop
Published: September 2023

Introduction

MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we report the case of a girl with MIRAGE syndrome who presented with adrenal insufficiency and chronic diarrhea.

Case presentation

The patient was born at 29 + 6 weeks of gestational age with a birth weight of 656 g (<3p). Her height and head circumference were also <3p. At birth, she presented with respiratory distress, meconium staining, and pneumomediastinum, which were managed with high-frequency ventilation and empirical antibiotics. Physical examination showed generalized hyperpigmentation and normal female genitalia. A few days after birth, polyuria and hypotension developed, and laboratory findings revealed hypoglycemia, hyponatremia, and hyperkalemia. Plasma adrenocorticotropic hormone levels were elevated with low serum cortisol levels and high plasma renin activity, which were suggestive of adrenal insufficiency. Hydrocortisone and fludrocortisone were introduced and maintained, and hyperpigmentation attenuated with time. Both kidneys looked dysplastic, and adrenal glands could not be traced on abdominal ultrasound. From the early days of life, thrombocytopenia and anemia were detected, but not to life-threatening level and slowly recovered up to the normal range. Despite aggressive nutritional support, weight gain and growth spurt were severely retarded during the hospital stay. Additionally, after introducing enteral feeding, she experienced severe diarrhea and subsequent perineal skin rashes and ulcerations. Fecal calprotectin level was highly elevated; however, a small bowel biopsy resulted in non-specific submucosal congestion. The patient was diagnosed with MIRAGE syndrome with SAMD9 gene mutation. She was discharged with tube feeding and elemental formula feeding continued, but chronic diarrhea persisted. By the time of the last follow-up at 15 months of corrected age, she was fortunately not subjected to severe invasive infection and myelodysplastic syndrome. However, she was dependent on tube feeding and demonstrated a severe developmental delay equivalent to approximately 5–6 months of age.

Conclusion

The early diagnosis of adrenal crisis and hormone replacement therapy can save the life of -patients with MIRAGE syndrome; however, chronic intractable diarrhea and growth and developmental delay continue to impede the patient’s well-being.
Effect of environmental integrity on the functional composition of the Odonata (Insecta) community in streams in the Eastern Amazon
Authors: Rocha Tainã Silva , Calvão Lenize Batista , Juen Leandro , Oliveira-Junior José Max Barbosa
Published: September 2023

Anthropic activities affect the dynamics of aquatic communities and can influence the reproductive behavior of many species. In addition, functional diversity is expected to be influenced by the environment. In this context, we evaluated how the biological functional characteristics of the Odonata adult community respond to impacts caused by human action on streams in the Eastern Amazon, using bionomic characteristics as response variables. Concomitantly, we analyzed which characteristics are responsible for the presence of species in the environment. We sampled adults of Odonata in 98 preserved and altered streams in the Eastern Amazon. We used as functional characteristics: oviposition, thermoregulation and body size, and as morphological characteristics: width of the thorax, width of the wing at the base, length of the abdomen and length of the thorax. We recorded 80 species, distributed in 16 functional groups and three categories: present in all environments, present only in preserved environments, and present only in altered environments. There was variation in the functional characteristics studied between the environments (PerMANOVA; F = 15,655; P < 0.01), with a significant difference in the composition of attributes between the environments studied. Although PCoA did not find a strong relationship between the functional attributes and the level of integrity, the individuals found in altered areas are heliothermic, exophytic oviposition, with a wider wing width at the base and larger size. Individuals with smaller body size and endophytic and epiphytic oviposition, and thermal and endothermic conformators are found in preserved areas. Our study provides evidence that functional attributes are determining factors for the occurrence of species in the environment. The high quality of environment has a significant effect on the composition of functional groups. Exophytic and heliothermic species are favored by altered environments, while in preserved environments, the species that are best adapted are those that present epiphytic and endophytic oviposition and ectothermic thermoregulation (thermal conformers). As for morphology, altered environments favor medium to large individuals, with greater thorax length and abdomen size, preserved environments may favor the smaller and/or specialized species.
A review of machine learning models applied to genomic prediction in animal breeding
Authors: Chafai Narjice , Hayah Ichrak , Houaga Isidore , Badaoui Bouabid
Published: September 2023

The advent of modern genotyping technologies has revolutionized genomic selection in animal breeding. Large marker datasets have shown several drawbacks for traditional genomic prediction methods in terms of flexibility, accuracy, and computational power. Recently, the application of machine learning models in animal breeding has gained a lot of interest due to their tremendous flexibility and their ability to capture patterns in large noisy datasets. Here, we present a general overview of a handful of machine learning algorithms and their application in genomic prediction to provide a meta-picture of their performance in genomic estimated breeding values estimation, genotype imputation, and feature selection. Finally, we discuss a potential adoption of machine learning models in genomic prediction in developing countries. The results of the reviewed studies showed that machine learning models have indeed performed well in fitting large noisy data sets and modeling minor nonadditive effects in some of the studies. However, sometimes conventional methods outperformed machine learning models, which confirms that there’s no universal method for genomic prediction. In summary, machine learning models have great potential for extracting patterns from single nucleotide polymorphism datasets. Nonetheless, the level of their adoption in animal breeding is still low due to data limitations, complex genetic interactions, a lack of standardization and reproducibility, and the lack of interpretability of machine learning models when trained with biological data. Consequently, there is no remarkable outperformance of machine learning methods compared to traditional methods in genomic prediction. Therefore, more research should be conducted to discover new insights that could enhance livestock breeding programs.
Using the community-based breeding program (CBBP) model as a collaborative platform to develop the African Goat Improvement Network—Image collection protocol (AGIN-ICP) with mobile technology for data collection and management of livestock phenotypes
Authors: Woodward-Greene M. Jennifer , Kinser Jason M. , Huson Heather J. , Sonstegard Tad S. , Soelkner Johann , Vaisman Iosif I. , Boettcher Paul , Masiga Clet W. , Mukasa Christopher , Abegaz Solomon , Agaba Morris , Ahmed Sahar S. , Maminiaina Oliver F. , Getachew Tesfaye , Gondwe Timothy N. , Haile Aynalem , Hassan Yassir , Kihara Absolomon , Kouriba Aly , Mruttu Hassan A. , Mujibi Denis , Nandolo Wilson , Rischkowsky Barbara A. , Rosen Benjamin D. , Sayre Brian , Taela Maria , Van Tassell Curtis P.
Published: September 2023

Introduction: The African Goat Improvement Network Image Collection Protocol (AGIN-ICP) is an accessible, easy to use, low-cost procedure to collect phenotypic data via digital images. The AGIN-ICP collects images to extract several phenotype measures including health status indicators (anemia status, age, and weight), body measurements, shapes, and coat color and pattern, from digital images taken with standard digital cameras or mobile devices. This strategy is to quickly survey, record, assess, analyze, and store these data for use in a wide variety of production and sampling conditions.

Methods: The work was accomplished as part of the multinational African Goat Improvement Network (AGIN) collaborative and is presented here as a case study in the AGIN collaboration model and working directly with community-based breeding programs (CBBP). It was iteratively developed and tested over 3 years, in 12 countries with over 12,000 images taken.

Results and discussion: The AGIN-ICP development is described, and field implementation and the quality of the resulting images for use in image analysis and phenotypic data extraction are iteratively assessed. Digital body measures were validated using the PreciseEdge Image Segmentation Algorithm (PE-ISA) and software showing strong manual to digital body measure Pearson correlation coefficients of height, length, and girth measures (0.931, 0.943, 0.893) respectively. It is critical to note that while none of the very detailed tasks in the AGIN-ICP described here is difficult, every single one of them is even easier to accidentally omit, and the impact of such a mistake could render a sample image, a sampling day’s images, or even an entire sampling trip’s images difficult or unusable for extracting digital phenotypes. Coupled with tissue sampling and genomic testing, it may be useful in the effort to identify and conserve important animal genetic resources and in CBBP genetic improvement programs by providing reliably measured phenotypes with modest cost. Potential users include farmers, animal husbandry officials, veterinarians, regional government or other public health officials, researchers, and others. Based on these results, a final AGIN-ICP is presented, optimizing the costs, ease, and speed of field implementation of the collection method without compromising the quality of the image data collection.
Maternal body fluid lncRNAs serve as biomarkers to diagnose ventricular septal defect: from amniotic fluid to plasma
Authors: Wang Huaming , Lin Xi , Wang Xinda , Liu Xinxiu , He Shaozheng , Lyu Guorong
Published: September 2023

Background: Maternal body fluids contain abundant cell-free fetal RNAs which have the potential to serve as indicators of fetal development and pathophysiological conditions. In this context, this study aimed to explore the potential diagnostic value of maternal circulating long non-coding RNAs (lncRNAs) in ventricular septal defect (VSD).

Methods: The potential of lncRNAs as non-invasive prenatal biomarkers for VSD was evaluated using quantitative polymerase chain reaction (qPCR) and receiver operating characteristic (ROC) curve analysis. The biological processes and regulatory network of these lncRNAs were elucidated through bioinformatics analysis.

Results: Three lncRNAs (LINC00598, LINC01551, and GATA3-AS1) were found to be consistent in both maternal plasma and amniotic fluid. These lncRNAs exhibited strong diagnostic performance for VSD, with AUC values of 0.852, 0.957, and 0.864, respectively. The bioinformatics analysis revealed the involvement of these lncRNAs in heart morphogenesis, actin cytoskeleton organization, cell cycle regulation, and protein binding through a competitive endogenous RNA (ceRNA) network at the post-transcriptional level.

Conclusion: The cell-free lncRNAs present in the amniotic fluid have the potential to be released into the maternal circulation, making them promising candidates for investigating epigenetic regulation in VSD.
ER stress: an emerging regulator in GVHD development
Authors: Choi Hee-Jin , Yu Xue-Zhong
Published: September 2023

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient’s cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.
Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis
Authors: Vlad Benjamin , Reichen Ina , Neidhart Stephan , Hilty Marc , Lekaditi Dimitra , Heuer Christine , Eisele Amanda , Ziegler Mario , Reindl Markus , Lutterotti Andreas , Regeniter Axel , Jelcic Ilijas
Published: September 2023

Background

Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS.

Methods

This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z).

Results

MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00).

Conclusion

Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.
Recent advances in mRNA cancer vaccines: meeting challenges and embracing opportunities
Authors: Wang Bolin , Pei Jinli , Xu Shengnan , Liu Jie , Yu Jinming
Published: September 2023

Since the successful application of messenger RNA (mRNA) vaccines in preventing COVID-19, researchers have been striving to develop mRNA vaccines for clinical use, including those exploited for anti-tumor therapy. mRNA cancer vaccines have emerged as a promising novel approach to cancer immunotherapy, offering high specificity, better efficacy, and fewer side effects compared to traditional treatments. Multiple therapeutic mRNA cancer vaccines are being evaluated in preclinical and clinical trials, with promising early-phase results. However, the development of these vaccines faces various challenges, such as tumor heterogeneity, an immunosuppressive tumor microenvironment, and practical obstacles like vaccine administration methods and evaluation systems for clinical application. To address these challenges, we highlight recent advances from preclinical studies and clinical trials that provide insight into identifying obstacles associated with mRNA cancer vaccines and discuss potential strategies to overcome them. In the future, it is crucial to approach the development of mRNA cancer vaccines with caution and diligence while promoting innovation to overcome existing barriers. A delicate balance between opportunities and challenges will help guide the progress of this promising field towards its full potential.
Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy
Authors: Holay Nisha , Somma Alexander , Duchow Mark , Soleimani Milad , Capasso Anna , Kottapalli Srividya , Rios Joshua , Giri Uma , Diamond Jennifer , Schreiber Anna , Piscopio Anthony D. , Van Den Berg Carla , Eckhardt S. Gail , Triplett Todd A.
Published: September 2023

Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy. In this study, we evaluated T cell responses to a novel class-selective HDACi (OKI-179, bocodepsin) by assessing histone acetylation levels, which revealed rapid responsiveness accompanied by an increase in CD4 and CD8 T cell frequencies in the blood. However, these rapid responses were transient, as histone acetylation and frequencies waned within 24 hours. This contrasts with in vitro models where high acetylation was sustained and continuous exposure to HDACi suppressed cytokine production. In vivo comparisons demonstrated that stopping OKI-179 treatment during PD-1 blockade was superior to continuous treatment. These findings provide novel insight into the direct effects of HDAC inhibitors on T cells and that treatment schedules that take into account acute T cell effects should be considered when combined with immunotherapies in order to fully harness the tumor-specific T cell responses in patients.
Interactive effects of salinity, temperature and food web configuration on performance and harmfulness of the raphidophyte Heterosigma akashiwo
Authors: Giesler Jakob Karl , Lemley Daniel Alan , Adams Janine Barbara , Moorthi Stefanie Devi
Published: September 2023

The cosmopolitan raphidophyte Heterosigma akashiwo commonly forms harmful algal blooms (HABs) in diverse estuaries discharging into Algoa Bay, South Africa, potentially leading to hypoxia, fish kills and a decline in key primary consumers. Despite the high environmental variability in these estuaries, little is known about how abiotic factors such as temperature and salinity constrain bloom formation and harmfulness of H. akashiwo. The present study therefore investigates growth, competition, and grazing interactions of H. akashiwo in laboratory experiments in response to two naturally relevant levels of salinity (15, 30) and temperature (16, 22°C), respectively. Experiments were set up with the naturally co-occurring dinoflagellate competitor Heterocapsa rotundata and two estuarine microzooplankton consumers, i.e., nauplii of the copepod Acartia tonsa and the rotifer Brachionus plicatilis. In monoculture, H. akashiwo growth was promoted at high temperature – low salinity conditions, while H. rotundata thrived under low temperature – high salinity conditions. In polyculture, H. akashiwo dominated at high temperature irrespective of the salinity regime, while at low temperature, it only dominated at low salinity and was suppressed by H. rotundata at high salinity. Grazing assays revealed highly negative effects of H. akashiwo on copepod nauplii survival and growth as well as mucus-induced immobilization, especially at high temperatures in combination with low salinity, while the estuarine adapted rotifers showed highest mortalities at the higher salinity level. The presence of H. rotundata significantly alleviated the harmful effects of H. akashiwo on both grazers, and the selectively feeding copepod nauplii actively avoided H. akashiwo when non-harmful prey was present. Overall, this study demonstrates that population dynamics and harmful effects of H. akashiwo are interactively determined by both abiotic conditions and food web configuration, implying competitor and consumer specific tolerances to the abiotic environment and their susceptibility to the harmful alga H. akashiwo.
An efficient mutagenesis system to improve the propamocarb tolerance in Lecanicillium lecanii (Zimmermann) Zare & Gams
Authors: Zhang Yanjun , Zhang Xiao , Qiu Weiliang
Published: September 2023

Lecanicillium lecanii (Zimmermann) Zare & Gams is used as an effective biopesticide for the control of sap-sucking insect pests on agricultural crops. However, low fungicide tolerance limits its large-scale field application. To improve the propamocarb tolerance in L. lecanii, a composite mutagenesis system was established by using UV-light (U), N-Methyl-N′-nitro-N-nitrosoguanidine (NTG) (N) and N+ ion-beam (I). The permutation type of three agents was a consecutive mutagenesis treatment (I/N/U) after an intermittent treatment (U + N + I). The “U” mutagenesis was performed at 254 nm for 60 s and at a distance of 45 cm under a 20 W germicidal lamp, the “N” mutagenesis was performed at a concentration of 1.0 mg/mL NTG for 60 min, and the “I” mutagenesis was performed by low energy N+ ion-beam using a dose of 10 × 1013 ions/cm2 at 30 keV. This composite mutagenesis system was recorded as the “U + N + I + I/N/U,” and then the mutagenesis efficiency in improving propamocarb tolerance was assessed by analyzing changes of mutants in the propamocarb sensitivity, mitotic stability, mycelial growth speed on plates or in liquid, sporulation on plates or aphids, conidial germination, 50% lethal concentration (LC50) and 50% lethal time (LT50) to aphids, lipid constituent and cell membrane permeability and control against aphids in the presence or absence of propamocarb. Compared to the wild-type isolate with a 50% effective concentration (EC50) value of 503.6 μg/mL propamocarb, the Ll-IC-UNI produced by the “U + N + I + I/N/U” had the highest EC50 value of 3576.4 μg/mL and a tolerance ratio of 7.1. The mutant was mitotically stable in 20-passage cultivation and did not show any unfavorable changes in growth and virulence indicators. The mutant showed the highest ability to resist or avoid the damaging effects of propamocarb as reflected by the alternations of lipid constituents and membrane permeability. The interval time for applying fungal agent was significantly shortened in this mutant after spraying a field recommended dose of 550 μg/mL propamocarb. In conclude, the “U + N + I + I/N/U” composite mutagenesis mode was efficient and useful to improve the propamocarb-tolerance of L. lecanii and the obtained Ll-IC-UNI could have commercial potential for field application.
Prolidase-proline oxidase axis is engaged in apoptosis induction by birch buds flavonol santin in endometrial adenocarcinoma cell line
Authors: Szoka Lukasz , Nazaruk Jolanta , Giegiel Joanna , Isidorov Valery
Published: September 2023

Cancer of the corpus uteri and cervix uteri, collectively ranks second among new cancer cases in women after breast cancer. Therefore, investigation of new anticancer agents and identifying new molecular targets presents a challenge to improve effectiveness of chemotherapy. In this study, antiproliferative activity of flavonoids derived from the buds of silver birch and downy birch was evaluated in endometrial cancer Ishikawa cells and cervical cancer HeLa cells. It was found that flavanol santin reduced viability of both cell lines better than other flavonoids, including apigenin and luteolin. Moreover, this activity was slightly higher than that induced by the chemotherapy drug, cisplatin. Santin promoted intrinsic and extrinsic apoptosis pathways in cancer cells, but it had low toxicity in normal fibroblasts. The mechanisms of impairing cancer cell viability included induction of oxidative proline catabolism, however in different ways in the cell lines used. In HeLa cells, increase of proline oxidation was due to activation of p53 leading to proline oxidase upregulation. In contrast, in Ishikawa cells, having basal proline oxidase level significantly higher than HeLa cells, santin treatment decreased its expression. Nevertheless, proline oxidation was induced in these cells since santin increased expression and activity of prolidase, an enzyme providing proline from protein degradation. In both cell lines, proline oxidation was associated with generation of reactive oxygen species leading to reduction in cell viability. Our findings reveal the involvement of proline oxidase in induction of apoptosis by santin and identify a role of prolidase in proline oxidase-dependent apoptosis.
Safety perception in patients with advanced idiopathic Parkinson’s disease – a qualitative study
Authors: Pedrosa Anna J. , van Munster Marlena , Timmermann Lars , Pedrosa David J.
Published: September 2023

Background

A fundamental cornerstone of quality of healthcare is patient safety, which many people with life-limiting illnesses feel is being compromised. Perceptions of impaired safety are associated with the occurrence of psychological distress and healthcare utilization. However, little is known about how people with idiopathic Parkinson’s disease (iPD) perceive their own safety toward the end of life. The aim of our study was therefore to investigate factors that influence the perception of safety of patients with advanced iPD.

Methods

We conducted semi-structured interviews with a purposeful sample of 21 patients with advanced iPD. Participants were recruited at the neurology department of a tertiary care hospital in Germany between August 2021 and June 2022. Data were analyzed using reflexive thematic analysis.

Results

iPD-patients reported relevant impairment of their safety. While most participants expressed safety concerns based on the manifestation of disease, our analysis identified enablers and barriers to establishing safety in patients with advanced iPD, in 10 additional domains: relationship to the disease, informedness, self-perception, utilization of support and care structures, healthcare professionals and structures, treatment, social interaction, social security, spirituality, and environment.

Conclusion

This study provides new insights into safety perceptions of patients with advanced iPD, which extend well beyond the physical realm. The findings suggest that clinicians and policy makers should consider a holistic and multidisciplinary approach to assessing and improving patients’ safety taking into account the enablers and barriers identified in this study.
Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software
Authors: de Villers-Sidani Étienne , Voss Patrice , Bastien Natacha , Cisneros-Franco J. Miguel , Hussein Shamiza , Mayo Nancy E. , Koch Nils A. , Drouin-Picaro Alexandre , Blanchette François , Guitton Daniel , Giacomini Paul S.
Published: September 2023

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.