bluuebunny/crossref_metadata_2025 huggingface dataset:
Robot reads ads: likability of calm and energetic audio advertising styles transferred to synthesized voices
Authors: Pajupuu Hille , Pajupuu Jaan , Altrov Rene , Kiissel Indrek
Published: April 2023

The increasing prevalence of audio advertising has provided a challenge to find out more about voices and performance styles used in advertisements. In this study, we were interested in the listeners' preferences when a synthesizer performs the advertisements. As training an advertisement style synthesizer requires big corpora, the creation of which is time-consuming and expensive, we have chosen to use less resource-intensive style transfer on already extant synthesized voices trained on neutral speech. We used a corpus of advertisements created out of 120 male and 120 female voices reading one text in both an energetic and calm advertisement style, the styles most commonly provided by advertising agencies, to train four style transfer models: energetic and calm for both male and female voices. These were used to convert two synthesized female and two male voices that had been created using a Merlin-based speech synthesizer for Estonian. Each converted voice performed three short advertisements. Adult listeners rated the likability of the performances on a 7-point Likert scale. The results showed that the calm performance style was overwhelmingly preferred. We also ascertained the acoustic features of the calm and energetic performances using the open-source toolkit openSMILE to calculate the 88 parameters of the extended Geneva Minimalistic Acoustic Parameter Set. The calm style differed from the energetic in acoustic features that are related to a lower, quieter, and more sonorous voice and a more neutral speaking style. Considering the difference in style ratings, it is worth taking the target audiences' style preferences into account.
Next-generation networks: Necessity of edge sharing
Authors: Lehr William , Stocker Volker
Published: April 2023

Resource sharing is fundamental to the design of telecommunication networks. The technology, economic and policy forces shaping the transition to next-generation digital networking infrastructure—characterized here as “5G+” (for 5G and beyond)—make new and evolved forms of edge sharing a necessity. Despite this necessity, most of the economic and policy research on Network Sharing Agreements (NSAs) has focused on sharing among service providers offering retail services via networks owned and operated by legacy fixed and mobile network operators (MNOs). In this essay, we make the case for why increased and more dynamic options for sharing, in particular of end-user owned network infrastructure, should be embraced for the future of NSAs. Furthermore, we explain how such a novel sharing paradigm must be matched by appropriate regulatory policies.
Non-invasive detection of severe PH in lung disease using magnetic resonance imaging
Authors: Alkhanfar Dheyaa , Dwivedi Krit , Alandejani Faisal , Shahin Yousef , Alabed Samer , Johns Chris , Garg Pankaj , Thompson A. A. Roger , Rothman Alexander M. K. , Hameed Abdul , Charalampopoulos Athanasios , Wild Jim M. , Condliffe Robin , Kiely David G. , Swift Andrew J.
Published: April 2023

Introduction

Severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg) in chronic lung disease (PH-CLD) is associated with high mortality and morbidity. Data suggesting potential response to vasodilator therapy in patients with PH-CLD is emerging. The current diagnostic strategy utilises transthoracic Echocardiography (TTE), which can be technically challenging in some patients with advanced CLD. The aim of this study was to evaluate the diagnostic role of MRI models to diagnose severe PH in CLD.

Methods

167 patients with CLD referred for suspected PH who underwent baseline cardiac MRI, pulmonary function tests and right heart catheterisation were identified. In a derivation cohort (n = 67) a bi-logistic regression model was developed to identify severe PH and compared to a previously published multiparameter model (Whitfield model), which is based on interventricular septal angle, ventricular mass index and diastolic pulmonary artery area. The model was evaluated in a test cohort.

Results

The CLD-PH MRI model [= (−13.104) + (13.059 * VMI)—(0.237 * PA RAC) + (0.083 * Systolic Septal Angle)], had high accuracy in the test cohort (area under the ROC curve (0.91) (p < 0.0001), sensitivity 92.3%, specificity 70.2%, PPV 77.4%, and NPV 89.2%. The Whitfield model also had high accuracy in the test cohort (area under the ROC curve (0.92) (p < 0.0001), sensitivity 80.8%, specificity 87.2%, PPV 87.5%, and NPV 80.4%.

Conclusion

The CLD-PH MRI model and Whitfield model have high accuracy to detect severe PH in CLD, and have strong prognostic value.
Diabetes mellitus in peripheral artery disease: Beyond a risk factor
Authors: Singh Madhu V. , Dokun Ayotunde O.
Published: April 2023

Peripheral artery disease (PAD) is one of the major cardiovascular diseases that afflicts a large population worldwide. PAD results from occlusion of the peripheral arteries of the lower extremities. Although diabetes is a major risk factor for developing PAD, coexistence of PAD and diabetes poses significantly greater risk of developing critical limb threatening ischemia (CLTI) with poor prognosis for limb amputation and high mortality. Despite the prevalence of PAD, there are no effective therapeutic interventions as the molecular mechanism of how diabetes worsens PAD is not understood. With increasing cases of diabetes worldwide, the risk of complications in PAD have greatly increased. PAD and diabetes affect a complex web of multiple cellular, biochemical and molecular pathways. Therefore, it is important to understand the molecular components that can be targeted for therapeutic purposes. In this review, we describe some major developments in enhancing the understanding of the interactions of PAD and diabetes. We also provide results from our laboratory in this context.
FDA regulations and prescription digital therapeutics: Evolving with the technologies they regulate
Authors: Watson Anthony , Chapman Richard , Shafai Gigi , Maricich Yuri A.
Published: April 2023

Technological progress in digital therapeutics—and, in particular prescription digital therapeutics (PDTs)—has outpaced the processes that the Food and Drug Administration (FDA) uses to regulate such products. Digital therapeutics have entered the health care ecosystem so rapidly that substantial misunderstandings exist about how they are evaluated and regulated by the FDA. This review briefly explains the relevant regulatory history of software as medical devices (SaMDs) and reviews the current regulatory landscape in which prescription and non-prescription digital therapeutics are developed and approved for use. These are important issues because PDTs, and digital therapeutics in general, are an explosively growing field in medicine and offer many advantages over conventional face-to-face treatments for the behavioral dimensions of a wide range of conditions and disease states. By allowing access to evidence-based therapies remotely and privately, digital therapeutics can reduce existing disparities in care and improve health equity. But clinicians, payers, and other healthcare stakeholders must appreciate the rigor of the regulatory frameworks within which PDTs are approved for use.
Looking for natural hydrogen in Albania and Kosova
Authors: Lévy Dan , Boka-Mene Molly , Meshi Avni , Fejza Islam , Guermont Thomas , Hauville Benoît , Pelissier Nicolas
Published: April 2023

A regional geochemistry field study was conducted in Albania and Kosova to spot natural H2 occurrences related to ophiolite massifs. A total of 21 sites, mainly consisting of natural springs, were studied, and nine were sampled for analyzing associated free gas and C and H isotopes of CH4 and H2 when possible. Four springs showed gas with H2 occurrence, one particularly reaching 16% of H2 in the north of Kosova in a location named Vuçe, which makes it the fifth gas seep most enriched in H2 in the Dinarides, after H2-rich gas seeps in Serbia and Bosnia and Herzegovina. This gas seep is associated with hyperalkaline water having a pH of about 10.7. This would favor the assumption that H2 is derived from the serpentinization of peridotites, a process which is likely still ongoing. H2 is associated mainly with N2 and CH4, like the other H2-rich gas springs in the Dinarides. Based on C and H isotopes, CH4 is abiotic or microbial. H isotopes suggest a formation of H2 at about a 2-km depth. Another hyperalkaline spring was found in the south of Albania, at the border of the Korça Basin, with less than 200 ppm of H2. No relation between H2 and He was identified at the scale of Albania and Kosova, nor at the scale of the whole Dinarides. This work provides a completed map of the H2 occurrences in the Dinarides and allows to highlight some hot spots for H2 exploration, mainly located inside the ophiolite massifs like in other ophiolites (such as Oman, New Caledonia, and The Philippines), and not on major faults like in the Pyrenees.
Fostering spatial ability development in and for authentic STEM learning
Authors: Zhu Caiwei , Leung Chloe Oi-Ying , Lagoudaki Eleni , Velho Mariana , Segura-Caballero Natalia , Jolles Dietsje , Duffy Gavin , Maresch Günter , Pagkratidou Marianna , Klapwijk Remke
Published: April 2023

Empirical interdisciplinary research has explored the role of spatial ability in STEM learning and achievement. While most of this research indicates that fostering spatial thinking in educational contexts has the potential to positively impact students’ enrollment and performance in STEM subjects, there is less agreement on the best approach to do so. This article provides an overview of various types of effective spatial interventions and practices in formal or informal educational contexts, including targeted training of STEM-relevant spatial skills, spatialized curricula embedded in schools, integrated STEM practices addressing students’ use of spatial skills, and spatial activities in informal STEM education. Gender and socio-economic status of students – two variables that have been found to moderate the relationship between students’ spatial ability and their STEM performance – are also discussed in this article. Drawing on a wide spectrum of perspectives on situating spatial ability research in STEM education contexts, this article underscores the need for further inquiry into opportunities for developing K-12 students’ spatial ability through integrated and informal STEM practices. This article proposes a conjecture that the relationship between developing students’ spatial ability and enhancing their abilities to solve spatially complex STEM problems is bidirectional. Recommendations for future research are made on lingering questions about the effect of interventions, untapped resources for spatial ability training in formal and informal STEM education, and educational strategies for developing students’ spatial ability in authentic learning environments.
Medical treatment of Cushing’s disease with concurrent diabetes mellitus
Authors: Mehlich Anna , Bolanowski Marek , Mehlich Dawid , Witek Przemysław
Published: April 2023

Cushing’s disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.
Effects of increased phosphorus fertilizer on C, N, and P stoichiometry in different organs of bluegrass (Poa L.) at different growth stages
Authors: Wang Jiahao , He Keyan , Bao Gensheng , He Lin , Xu Hang , Song Meiqi , Jin Ling , Wei Xiaoxing
Published: April 2023

Introduction

The application of phosphorus (P) fertilizer can promote photosynthesis in forage grasses and accelerate their establishment.

Methods

To improve the utilization efficiency of P fertilizer for bluegrass (Poa L.) in alpine regions, the effects of P fertilizer on their growth, and carbon (C), nitrogen (N) and P distribution in their different organs of them are tested at six P fertilization levels (3, 6, 9, 12, 15, 18 g·m−2).

Results

(1) The nutrient content in each organ of bluegrass varies during different growth stages, with the lowest nutrient content occurring in the wilt stage. (2) The response of the nutrient content and ratio of each organ of bluegrass to different P fertilization levels varies. When the P application rate was 15 g·m−2, the contents of N and P in roots were the highest, and their C/N and C/P ratios were the lowest. When the P application rate was 12 g·m−2, the contents of N and P in the stems were the highest, and their C/N and C/P ratios were the lowest. When the P application rate was 9 g·m−2, the contents of N and P in leaves were the highest, and their C/N and C/P ratios were the lowest. When the P application rate was 6 g·m−2 the contents of N and P in the panicle were the highest, and their C/N and C/P ratios were the lowest.

Discussion

These results provide a better understanding of the effect of P fertilization in the nutrient partitioning pattern of perennial forage plant organs in alpine regions. The information from this study can support a more reasonable P fertilization for the establishment of early grassland. For example, in artificial forage grassland, the application of low-concentration P fertilizer (6~9 g·m−2) can promote the nutrient content in spikes and stems of forage grass; for ecological management, the application of high-concentration P fertilizer (15 g·m−2) can promote the nutrient content in roots and enhance the ecological benefits of forage grassland.
Effects of predation risks of bats on the growth, development, reproduction, and hormone levels of Spodoptera litura
Authors: Zhang Wenjun , Liu Yingying , Wang Zhiqiang , Lin Tingting , Feng Jiang , Jiang Tinglei
Published: April 2023

Predation is a powerful selection pressure that shapes predator–prey interactions. Due to long-term interactions, moths have developed hearing to detect the echolocation calls of bats. This allows bats to impose the non-consumptive effects of predation on moths. However, information on the changes in the growth, development, reproduction, and hormones of moths that are vulnerable to bat predation is limited. In this study, we used Spodoptera litura (Lepidoptera: Noctuidae) to determine the effects of the predation risks of bats on their growth, development, reproduction, and hormone titers. Our results showed that the larvae of S. litura increased food intake, accelerated the development of the larval stages, increased mortality and metamorphosis failure, and had a smaller body size under the risk of predation by bats. Additionally, the reproductive activity and fecundity decreased in the adults of S. litura, but the juvenile hormone titers and 20-Ecdydysone hormone titers increased. These results suggested an adaptive response in S. litura under bat predation risks at the cost of lower survival and reproduction. Finally, we found that S. litura moths showed different responses to different predation risk cues, which suggested that they might assess the magnitude of different predation risks to make the most suitable decision for survival and reproduction. Our results highlight the importance of the predation risk imposed by bats to negatively regulate the population dynamics of moths. Our findings indicated that the biological control of bugs using bats is a promising strategy.
Study on fractional vegetation cover dynamic in the Yellow River Basin, China from 1901 to 2100
Authors: Jian Shengqi , Shi Sijia , Cui Jingkai , Zhu Tiansheng , Hu Caihong
Published: April 2023

Increasing climate change makes vegetation dynamic. At the same time, dynamic changes in vegetation not only have a feedback effect on climate change, but also affect the hydrological cycle process. Therefore, understanding the vegetation change and its response to climate change is a priority for predicting future climate change and studying the impact of vegetation change on the hydrological cycle. In this study, the Yellow River Basin in China is the study area. Based on the analysis of the evolution characteristics of meteorological elements and fractional vegetation cover (FVC), the delta downscaling Coupled Model Intercomparison Project Phase 6 (CMIP6) models are optimized. The empirical orthogonal function (EOF) and singular value decomposition (SVD) methods are used to investigate the impact of climate change on vegetation in the Yellow River Basin. The results show that: (1) in the four scenarios (SSP126, SSP245, SSP370, and SSP585), FVC in the Yellow River Basin from 2022 to 2100 shows an increasing trend, SSP370 (0.017 10a–1) > SSP126 (0.014 10a–1) > SSP245 (0.0087 10a–1) > SSP585 (0.0086 10a–1). Spatially, FVC in most regions of the Yellow River Basin show an increasing trend under the four scenarios, and the degraded areas are concentrated in a small part of the Yellow River headwaters. (2) There is a significant positive correlation between FVC and precipitation (Pre) and temperature (Tem) under four scenarios in the Yellow River Basin from 2022 to 2100. Under the same scenario, the annual average temperature can be considered as the dominant factor of FVC change in the Yellow River Basin. Under different scenarios, the impact of climate change on FVC under the high emission scenarios is greater than that under the low emission scenarios. This study will help to better understand the response of vegetation to climate change and provide a scientific basis for formulating ecological protection measures to cope with future climate change in the Yellow River Basin.
Radiation and temperature dominate the spatiotemporal variability in resilience of subtropical evergreen forests in China
Authors: Chen Jinghua , Wang Shaoqiang , Shi Hao , Chen Bin , Wang Junbang , Zheng Chen , Zhu Kai
Published: April 2023

Forest resilience is crucial to the mitigation of climate change, due to the enormous potential of forests to reduce atmospheric carbon dioxide concentrations and the possible conversion of forests from net carbon sinks into carbon sources following external disturbances. Subtropical forests are suffering the highest rates of forest change, but how they are evolving in response to climate change is little known. In this study, we estimated the spatial pattern and temporal trend of the resilience of subtropical evergreen forests in China by applying the lag-one autocorrelation (AC1) method to satellite kernel normalized difference vegetation index (kNDVI) data over the past two decades and identified the influential environmental factors that affect the ecosystem resilience by developing random forest (RF) regression models. The computed long-term AC1 based on kNDVI for the 2001–2020 period depicts considerable spatial variability in the resilience of the subtropical evergreen forests in China, with lower resilience at lower latitudes. The RF regression analysis suggests that the spatial variability in the forest resilience can be re-established by forest and climatic variables, and is largely affected by climate, with the three most influential variables being solar radiation (SR, %incMSE = 20.7 ± 1.8%), vapor pressure deficit (VPD, %incMSE = 13.8 ± 0.2%) and minimum temperature (Tmin, %incMSE = 13.3 ± 1.2%). Higher forest resilience is more likely to be located in areas with less radiation stress, adequate water availability, and less warming. Trend analysis shows a declining trend for the resilience of subtropical evergreen forests in China since the 2000s but an increasing forest resilience in the last decade, which is mainly dominated by temperature changes, including average and minimum temperatures. Considering the expected warming-dominated period in times of rapid climatic change, we suggest potential critical responses for subtropical forest productivity to the disturbances should be of greater concern in the future.
Salinity stress endurance of the plants with the aid of bacterial genes
Authors: Zamanzadeh-Nasrabadi Seyyedeh Maryam , Mohammadiapanah Fatemeh , Hosseini-Mazinani Mehdi , Sarikhan Sajjad
Published: April 2023

The application of plant growth-promoting bacteria (PGPB) is vital for sustainable agriculture with continuous world population growth and an increase in soil salinity. Salinity is one of the severe abiotic stresses which lessens the productivity of agricultural lands. Plant growth-promoting bacteria are key players in solving this problem and can mitigate salinity stress. The highest of reported halotolerant Plant growth-promoting bacteria belonged to Firmicutes (approximately 50%), Proteobacteria (40%), and Actinobacteria (10%), respectively. The most dominant genera of halotolerant plant growth-promoting bacteria are Bacillus and Pseudomonas. Currently, the identification of new plant growth-promoting bacteria with special beneficial properties is increasingly needed. Moreover, for the effective use of plant growth-promoting bacteria in agriculture, the unknown molecular aspects of their function and interaction with plants must be defined. Omics and meta-omics studies can unreveal these unknown genes and pathways. However, more accurate omics studies need a detailed understanding of so far known molecular mechanisms of plant stress protection by plant growth-promoting bacteria. In this review, the molecular basis of salinity stress mitigation by plant growth-promoting bacteria is presented, the identified genes in the genomes of 20 halotolerant plant growth-promoting bacteria are assessed, and the prevalence of their involved genes is highlighted. The genes related to the synthesis of indole acetic acid (IAA) (70%), siderophores (60%), osmoprotectants (80%), chaperons (40%), 1-aminocyclopropane-1-carboxylate (ACC) deaminase (50%), and antioxidants (50%), phosphate solubilization (60%), and ion homeostasis (80%) were the most common detected genes in the genomes of evaluated halotolerant plant growth-promoting and salinity stress-alleviating bacteria. The most prevalent genes can be applied as candidates for designing molecular markers for screening of new halotolerant plant growth-promoting bacteria.
Metabolomic and transcriptomic responses of Adiantum (Adiantum nelumboides) leaves under drought, half-waterlogging, and rewater conditions
Authors: Liang Qianyan , Dun Bicheng , Li Linbao , Ma Xiaobo , Zhang Haibo , Su Yang , Wu Di
Published: April 2023

Introduction:Adiantum nelumboides (Adiantum) is an endangered fern with a narrow distribution along the Yangtze River in China. Due to its cliff-dwelling habit, it experiences water stress conditions, which further endangers its survival. However, no information is available about its molecular responses to drought and half-waterlogging conditions.

Methods: Here, we applied five and ten days of half-waterlogging stress, five days of drought stress, and rewatering after five days of drought stress, and studied the resulting metabolome profiles and transcriptome signatures of Adiantum leaves.

Results and Discussion: The metabolome profiling detected 864 metabolites. The drought and half-waterlogging stress induced up-accumulation of primary and secondary metabolites including amino acids and derivatives, nucleotides and derivatives, flavonoids, alkaloids, and phenolic acid accumulation in Adiantum leaves. Whereas, rewatering the drought-stressed seedlings reversed most of these metabolic changes. Transcriptome sequencing confirmed the differential metabolite profiles, where the genes enriched in pathways associated with these metabolites showed similar expression patterns. Overall, the half-waterlogging stress for 10 days induced large-scale metabolic and transcriptomic changes compared to half-waterlogging stress for 05 days, drought stress for 05 days or rewatering for 05 days.

Conclusion: This pioneering attempt provides a detailed understanding of molecular responses of Adiantum leaves to drought and half-waterlogging stresses and rewater conditions. This study also provides useful clues for the genetic improvement of Adiantum for drought/half-waterlogging stress tolerance.
Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren’s syndrome: evidence- and practice-based guidance
Authors: Marinho António , Delgado Alves José , Fortuna Jorge , Faria Raquel , Almeida Isabel , Alves Glória , Araújo Correia João , Campar Ana , Brandão Mariana , Crespo Jorge , Marado Daniela , Matos-Costa João , Oliveira Susana , Salvador Fernando , Santos Lelita , Silva Fátima , Fernandes Milene , Vasconcelos Carlos
Published: April 2023

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren’s syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts’ input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.
Sirtuins in osteoarthritis: current understanding
Authors: Liu Yikai , Zhang Zian , Liu Chang , Zhang Haining
Published: April 2023

Osteoarthritis (OA) is a common disease characterized by severe chronic joint pain, that imposes a large burden on elderly people. OA is a highly heterogeneous disease, and multiple etiologies contribute to its progression. Sirtuins (SIRTs) are Class III histone deacetylases (HDACs) that regulate a comprehensive range of biological processes such as gene expression, cell differentiation, and organism development, and lifespan. Over the past three decades, increasing evidence has revealed that SIRTs are not only important energy sensors but also protectors against metabolic stresses and aging, and an increasing number of studies have focused on the functions of SIRTs in OA pathogenesis. In this review, we illustrate the biological functions of SIRTs in OA pathogenesis from the perspectives of energy metabolism, inflammation, autophagy and cellular senescence. Moreover, we offer insights into the role played by SIRTs in regulating circadian rhythm, which has recently been recognized to be crucial in OA development. Here, we provide the current understanding of SIRTs in OA to guide a new direction for OA treatment exploration.
Polymorphisms in the MBL2 gene are associated with the plasma levels of MBL and the cytokines IL-6 and TNF-α in severe COVID-19
Authors: Queiroz Maria Alice Freitas , Santiago Angélica Menezes , Brito Wandrey Roberto dos Santos , Pereira Keise Adrielle Santos , de Brito William Botelho , Torres Maria Karoliny da Silva , Lopes Jeferson da Costa , Santos Erika Ferreira dos , da Costa Flávia Póvoa , de Sarges Kevin Matheus Lima , Cantanhede Marcos Henrique Damasceno , de Brito Mioni Thieli Figueiredo Magalhães , da Silva Andréa Luciana Soares , Leite Mauro de Meira , Viana Maria de Nazaré do Socorro de Almeida , Rodrigues Fabíola Brasil Barbosa , da Silva Rosilene , Viana Giselle Maria Rachid , Chaves Tânia do Socorro Souza , Veríssimo Adriana de Oliveira Lameira , Carvalho Mayara da Silva , Henriques Daniele Freitas , Santos Carla Pinheiro dos , Nunes Juliana Abreu Lima , Costa Iran Barros , Amoras Ednelza da Silva Graça , Lima Sandra Souza , Cayres-Vallinoto Izaura Maria Vieira , Brasil-Costa Igor , Quaresma Juarez Antônio Simões , Falcão Luiz Fábio Magno , Santos Eduardo José Melo dos , Vallinoto Antonio Carlos Rosário
Published: April 2023

Introduction

Mannose-binding lectin (MBL) promotes opsonization, favoring phagocytosis and activation of the complement system in response to different microorganisms, and may influence the synthesis of inflammatory cytokines. This study investigated the association of MBL2 gene polymorphisms with the plasma levels of MBL and inflammatory cytokines in COVID-19.

Methods

Blood samples from 385 individuals (208 with acute COVID-19 and 117 post-COVID-19) were subjected to real-time PCR genotyping. Plasma measurements of MBL and cytokines were performed by enzyme-linked immunosorbent assay and flow cytometry, respectively.

Results

The frequencies of the polymorphic MBL2 genotype (OO) and allele (O) were higher in patients with severe COVID-19 (p< 0.05). The polymorphic genotypes (AO and OO) were associated with lower MBL levels (p< 0.05). IL-6 and TNF-α were higher in patients with low MBL and severe COVID-19 (p< 0.05). No association of polymorphisms, MBL levels, or cytokine levels with long COVID was observed.

Discussion

The results suggest that, besides MBL2 polymorphisms promoting a reduction in MBL levels and therefore in its function, they may also contribute to the development of a more intense inflammatory process responsible for the severity of COVID-19.
Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands
Authors: Wakefield Devin L. , Golfetto Ottavia , Jorand Raphael , Biswas Sunetra , Meyer Kassondra , Avery Kendra N. , Zer Cindy , Cacao Eliedonna E. , Tobin Steven J. , Talisman Ian J. , Williams John C. , Jovanovic-Talisman Tijana
Published: April 2023

Introduction

The progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.

Methods

By combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.

Results

We detected marked changes to the cellular membrane organization of HER2 when cells were treated with therapeutic antibodies. When we compared untreated samples to four treatment scenarios, we observed the following HER2 membrane features: (1) the monovalent Fab domain of trastuzumab did not significantly affect HER2 clustering; (2) individual therapy with either trastuzumab or (3) pertuzumab produced significantly higher levels of HER2 clustering; (4) a combination of trastuzumab plus pertuzumab produced the highest level of HER2 clustering. To further enhance this last effect, we created multivalent ligands using meditope technology. Treatment with a tetravalent meditope ligand combined with meditope-enabled trastuzumab resulted in pronounced HER2 clustering. Moreover, compared to pertuzumab plus trastuzumab, at early time points this meditope-based combination was more effective at inhibiting epidermal growth factor (EGF) dependent activation of several downstream protein kinases.

Discussion

Collectively, mAbs and multivalent ligands can efficiently alter the organization and activation of the HER2 receptors. We expect this approach could be used in the future to develop new therapeutics.
Evaluation of learning outcomes of humanities curricula in medical students. A meta-review of narrative and systematic reviews
Authors: Coronado-Vázquez Valle , Antón-Rodríguez Cristina , Gómez-Salgado Juan , Ramírez-Durán María del Valle , Álvarez-Montero Santiago
Published: April 2023

Objectives

To assess the expected learning outcomes of medical humanities subjects in medical studies curricula. To connect those expected learning outcomes with the types of knowledge to be acquired in medical education.

Methods

Meta-review of systematic and narrative reviews. Cochrane Library, MEDLINE (Pubmed), Embase, CINAHL, and ERIC were searched. In addition, references from all the included studies were revised, and the ISI Web of Science and DARE were searched.

Results

A total of 364 articles were identified, of which six were finally included in the review. Learning outcomes describe the acquisition of knowledge and skills to improve the relationship with patients, as well as the incorporation of tools to reduce burnout and promote professionalism. Programs that focus on teaching humanities promote diagnostic observation skills, the ability to cope with uncertainty in clinical practice, and the development of empathetic behaviors.

Conclusion

The results of this review show heterogeneity in the teaching of medical humanities, both in terms of content and at the formal level. Humanities learning outcomes are part of the necessary knowledge for good clinical practice. Consequently, the epistemological approach provides a valid argument for including the humanities in medical curricula.
An autophagy-related diagnostic biomarker for uterine fibroids: FOS
Authors: Cai Lei , Li Jie , Long Rui , Liao Zhiqi , Gong Juejun , Zheng Bowen , Zhang Hanwang
Published: April 2023

Uterine fibroids (UFs) are the most common benign gynecologic tumors in reproductive-aged women. The typical diagnostic strategies of UFs are transvaginal ultrasonography and pathological feature, while molecular biomarkers are considered conventional options in the assessment of the origin and development of UFs in recent years. Here, we extracted the differential expression genes (DEGs) and differential DNA methylation genes (DMGs) of UFs from the Gene Expression Omnibus (GEO) database, GSE64763, GSE120854, GSE45188, and GSE45187. 167 DEGs with aberrant DNA methylation were identified, and further Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by the relevant R package. We next discerned 2 hub genes (FOS, and TNFSF10) with autophagy involvement by overlapping 167 DEGs and 232 autophagic regulators from Human Autophagy Database. FOS was identified as the most crucial gene through the Protein–Protein Interactions (PPI) network with the correlation of the immune scores. Moreover, the down-regulated expression of FOS in UFs tissue at both mRNA and protein levels was validated by RT-qPCR and immunohistochemistry respectively. The area under the ROC curve (AUC) of FOS was 0.856, with a sensitivity of 86.2% and a specificity of 73.9%. Overall, we explored the possible biomarker of UFs undergoing DNA—methylated autophagy and provided clinicians with a comprehensive assessment of UFs.
Risk factors and 180-day mortality of acute kidney disease in critically ill patients: A multi-institutional study
Authors: Pan Heng-Chih , Chen Hsing-Yu , Chen Hui-Ming , Huang Yu-Tung , Fang Ji-Tseng , Chen Yung-Chang
Published: April 2023

Background

Critically ill patients with acute kidney injury (AKI) have a poor prognosis. Recently, the Acute Disease Quality Initiative (ADQI) proposed to define acute kidney disease (AKD) as acute or subacute damage and/or loss of kidney function post AKI. We aimed to identify the risk factors for the occurrence of AKD and to determine the predictive value of AKD for 180-day mortality in critically ill patients.

Methods

We evaluated 11,045 AKI survivors and 5,178 AKD patients without AKI, who were admitted to the intensive care unit between 1 January 2001 and 31 May 2018, from the Chang Gung Research Database in Taiwan. The primary and secondary outcomes were the occurrence of AKD and 180-day mortality.

Results

The incidence rate of AKD among AKI patients who did not receive dialysis or died within 90 days was 34.4% (3,797 of 11,045 patients). Multivariable logistic regression analysis indicated that AKI severity, underlying early CKD, chronic liver disease, malignancy, and use of emergency hemodialysis were independent risk factors of AKD, while male gender, higher lactate levels, use of ECMO, and admission to surgical ICU were negatively correlated with AKD. 180-day mortality was highest among AKD patients without AKI during hospitalization (4.4%, 227 of 5,178 patients), followed by AKI with AKD (2.3%, 88 of 3,797 patients) and AKI without AKD (1.6%, 115 of 7,133 patients). AKI with AKD had a borderline significantly increased risk of 180-day mortality (aOR 1.34, 95% CI 1.00–1.78; p = 0.047), while patients with AKD but no preceding AKI episodes had the highest risk (aOR 2.25, 95% CI 1.71–2.97; p < 0.001).

Conclusion

The occurrence of AKD adds limited additional prognostic information for risk stratification of survivors among critically ill patients with AKI but could predict prognosis in survivors without prior AKI.
Development of a RPA-CRISPR-Cas12a Assay for Rapid, Simple, and Sensitive Detection of Mycoplasma hominis
Authors: Chen Jialing , Huang Yinger , Xiao Bin , Deng Hao , Gong Kunxiang , Li Kun , Li Linhai , Hao Wenbo
Published: April 2023

Graphical Abstract

Schematic of Mycoplasma hominis nucleic acid detection based on the CRISPR-Cas12a system. Clinical samples from cervical or urethral swabs were collected and incubated with lysis buffer to release nucleic acid (10 min). Extracted DNA (1 μl) is subjected to the RPA reaction with specific primers at 37°C. After 20 min, RPA product was subjected to the CRISPR-Cas12a reaction for cleavage. The collateral nuclease activity of Cas12a (250 nM) proteins were activated upon specific binding to crRNA (crRNA3, 62.5 nM) and the DNA product; thus, Cas12a cut the quenched fluorescent ssDNA reporter (125 nM) (30 min). The generated fluorescence signal would be measured by a fluorescence plate reader or visualized by lateral flow strips.
AMF species do matter: Rhizophagus irregularis and Funneliformis mosseae affect healthy and PVY-infected Solanum tuberosum L. in a different way
Authors: Deja-Sikora Edyta , Werner Klaudia , Hrynkiewicz Katarzyna
Published: April 2023

Arbuscular mycorrhizal fungi (AMF) were documented to positively influence plant growth and yield, which is extremely important for the production of many crops including potato. However, the nature of the interaction between arbuscular mycorrhiza and plant virus that share the same host is not well characterized. In this study, we examined the effect of different AMF, Rhizophagus irregularis and Funneliformis mosseae, on healthy and potato virus Y (PVY)-infected Solanum tuberosum L. The analyses conducted included the measurement of potato growth parameters, oxidative stress indicators, and photosynthetic capacity. Additionally, we evaluated both the development of AMF in plant roots and the virus level in mycorrhizal plants. We found that two AMF species colonized plant roots to varying degrees (ca. 38% for R. irregularis vs. 20% for F. mosseae). Rhizophagus irregularis had a more positive effect on potato growth parameters, causing a significant increase in the total fresh and dry weight of tubers, along with virus-challenged plants. Furthermore, this species lowered hydrogen peroxide levels in PVY-infected leaves and positively modulated the levels of nonenzymatic antioxidants, i.e., ascorbate and glutathione in leaves and roots. Finally, both fungal species contributed to reduced lipid peroxidation and alleviation of virus-induced oxidative damage in plant organs. We also confirmed an indirect interaction between AMF and PVY inhabiting the same host. The two AMF species seemed to have different abilities to colonize the roots of virus-infected hosts, as R. irregularis showed a stronger drop in mycorrhizal development in the presence of PVY. At the same time, arbuscular mycorrhiza exerted an effect on virus multiplication, causing increased PVY accumulation in plant leaves and a decreased concentration of virus in roots. In conclusion, the effect of AMF-plant interactions may differ depending on the genotypes of both symbiotic partners. Additionally, indirect AMF-PVY interactions occur in host plants, diminishing the establishment of arbuscular mycorrhiza while changing the distribution of viral particles in plants.
Regulatory mechanism of trichothecene biosynthesis in Fusarium graminearum
Authors: Liew Maydelene Xiao Xuan , Nakajima Yuichi , Maeda Kazuyuki , Kitamura Naotsugu , Kimura Makoto
Published: April 2023

Among the genes involved in the biosynthesis of trichothecene (Tri genes), Tri6 and Tri10 encode a transcription factor with unique Cys2His2 zinc finger domains and a regulatory protein with no consensus DNA-binding sequences, respectively. Although various chemical factors, such as nitrogen nutrients, medium pH, and certain oligosaccharides, are known to influence trichothecene biosynthesis in Fusarium graminearum, the transcriptional regulatory mechanism of Tri6 and Tri10 genes is poorly understood. Particularly, culture medium pH is a major regulator in trichothecene biosynthesis in F. graminearum, but it is susceptible to metabolic changes posed by nutritional and genetic factors. Hence, appropriate precautions should be considered to minimize the indirect influence of pH on the secondary metabolism while studying the roles of nutritional and genetic factors on trichothecene biosynthesis regulation. Additionally, it is noteworthy that the structural changes of the trichothecene gene cluster core region exert considerable influence over the normal regulation of Tri gene expression. In this perspective paper, we consider a revision of our current understanding of the regulatory mechanism of trichothecene biosynthesis in F. graminearum and share our idea toward establishing a regulatory model of Tri6 and Tri10 transcription.
Yeast oral vaccines against infectious diseases
Authors: Austriaco Nicanor
Published: April 2023

Vaccines that are delivered orally have several advantages over their counterparts that are administered via injection. Despite the advantages of oral delivery, however, approved oral vaccines are currently limited either to diseases that affect the gastrointestinal tract or to pathogens that have a crucial life cycle stage in the gut. Moreover, all of the approved oral vaccines for these diseases involve live-attenuated or inactivated pathogens. This mini-review summarizes the potential and challenges of yeast oral vaccine delivery systems for animal and human infectious diseases. These delivery systems utilize whole yeast recombinant cells that are consumed orally to transport candidate antigens to the immune system of the gut. This review begins with a discussion of the challenges associated with oral administration of vaccines and the distinct benefits offered by whole yeast delivery systems over other delivery systems. It then surveys the emerging yeast oral vaccines that have been developed over the past decade to combat animal and human diseases. In recent years, several candidate vaccines have emerged that can elicit the necessary immune response to provide significant protection against challenge by pathogen. They serve as proof of principle to show that yeast oral vaccines hold much promise.
A review on nanoparticles: characteristics, synthesis, applications, and challenges
Authors: Altammar Khadijah A.
Published: April 2023

The significance of nanoparticles (NPs) in technological advancements is due to their adaptable characteristics and enhanced performance over their parent material. They are frequently synthesized by reducing metal ions into uncharged nanoparticles using hazardous reducing agents. However, there have been several initiatives in recent years to create green technology that uses natural resources instead of dangerous chemicals to produce nanoparticles. In green synthesis, biological methods are used for the synthesis of NPs because biological methods are eco-friendly, clean, safe, cost-effective, uncomplicated, and highly productive. Numerous biological organisms, such as bacteria, actinomycetes, fungi, algae, yeast, and plants, are used for the green synthesis of NPs. Additionally, this paper will discuss nanoparticles, including their types, traits, synthesis methods, applications, and prospects.
A whole cell-based Matrix-assisted laser desorption/ionization mass spectrometry lipidomic assay for the discovery of compounds that target lipid a modifications
Authors: Tang Wenhao , Osborne Joanne , Dortet Laurent , Larrouy-Maumus Gerald
Published: April 2023

Introduction

Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is a powerful analytical technique that has been applied to a wide variety of applications ranging from proteomics to clinical diagnostics. One such application is its use as a tool for discovery assays, such as monitoring the inhibition of purified proteins. With the global threat from antimicrobial-resistant (AMR) bacteria, new and innovative solutions are required to identify new molecules that could revert bacterial resistance and/or target virulence factors. Here, we used a whole cell-based MALDI-TOF lipidomic assay using a routine MALDI Biotyper Sirius system operating in linear negative ion mode combined with the MBT Lipid Xtract kit to discover molecules targeting bacteria that are resistant to polymyxins, which are considered last-resort antibiotics.

Methods

A library of 1200 natural compounds was tested against an E. coli strain expressing mcr-1, which is known to modify lipid A by adding phosphoethanolamine (pETN), making the strain resistant to colistin.

Results and Discussion

Using this approach, we identified 8 compounds that led to a decrease in this lipid A modification by MCR-1 and could potentially be employed to revert resistance. Taken together, as-proof-of-principle, the data we report here represent a new workflow based on the analysis of bacterial lipid A by routine MALDI-TOF for the discovery of inhibitors that could target bacterial viability and/or virulence.