bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hibberdia magna (Chrysophyceae): a promising freshwater fucoxanthin and polyunsaturated fatty acid producer
Authors: Střížek Antonín , Přibyl Pavel , Lukeš Martin , Grivalský Tomáš , Kopecký Jiří , Galica Tomáš , Hrouzek Pavel 
Published: April 2023

Abstract
Background
Algae are prominent producers of carotenoids and polyunsaturated fatty acids which are greatly prized in the food and pharmaceutic industry. Fucoxanthin represents a notable high-value carotenoid produced exclusively by algae. Its benefits range far beyond just antioxidant activity and include cancer prevention, anti-diabetes, anti-obesity, and many other positive effects. Accordingly, large-scale microalgae cultivation to produce fucoxanthin and polyunsaturated fatty acids is still under intensive development in the commercial and academic sectors. Industrially exploitable strains are predominantly derived from marine species while comparable freshwater fucoxanthin producers have yet to be explored.

Results
In this study, we searched for freshwater fucoxanthin producers among photoautotrophic flagellates including members of the class Chrysophyceae. The initial screening turned our attention to the chrysophyte alga Hibberdia magna. We performed a comprehensive cultivation experiments using a temperature × light cross-gradient to assess the impact of these conditions on the target compounds productivity. Here we present the observations that H. magna simultaneously produces fucoxanthin (max. 1.2% dry biomass) and polyunsaturated fatty acids (max. ~ 9.9% dry biomass) and is accessible to routine cultivation in lab-scale conditions. The highest biomass yields were 3.73 g L−1 accompanied by maximal volumetric productivity of 0.54 g L−1 d−1 which are comparable values to marine microalgae fucoxanthin producers in phototrophic mode. H. magna demonstrated different optimal conditions for biomass, fucoxanthin, and fatty acid accumulation. While maximal fucoxanthin productivities were obtained in dim light and moderate temperatures (23 °C× 80 µmol m−2 s−1), the highest PUFA and overall biomass productivities were found in low temperature and high light (17–20 °C × 320–480 µmol m−2 s−1). Thus, a smart biotechnology setup should be designed to fully utilize H. magna biotechnological potential.

Conclusions
Our research brings pioneer insight into the biotechnology potential of freshwater autotrophic flagellates and highlights their ability to produce high-value compounds. Freshwater fucoxanthin-producing species are of special importance as the use of sea-water-based media may increase cultivation costs and prohibits inland microalgae production.
The benefits and risks of nostalgia: analysis of a fictional case with special reference to ethical and existential issues
Authors: Bäckryd Emmanuel 
Published: April 2023

Abstract
Background
In a previous paper in Philos Ethics Humanit Med, the 1937 Swedish novel Sömnlös (Swedish for sleepless) by Vilhelm Moberg was used as background for a thought experiment, in which last century’s progresses concerning the safety of sleeping pills were projected into the future. This gave rise to a theoretical discussion about broad medico-philosophical questions such as (among other things) the concept of pharmaceuticalisation.

Methods
In this follow-up paper, the theme of insomnia in Sömnlös is complemented by a discussion of the concept of nostalgia. The core of the paper is a theoretical discussion about the benefits and risks of nostalgia, bringing together some aspects of recent psychological research about the construct of nostalgia with the main story line of the novel.

Results and Conclusion
Nostalgia is portrayed as being, in some sense at least, ultimately beneficial for the protagonist of Sömnlös. This is congruent with recent psychological research. However, the story also shows that nostalgia may lead to problematic behaviours, at least when viewed from a virtue ethics perspective. Hence, nostalgia is both what leads the protagonist into ethically problematic behaviour and that which (paradoxically) ultimately saves him from his initial lack of courage, justice, temperance and practical wisdom. Moreover, the protagonist does not only “grow” ethically but also existentially. Hence, the novel opens up the possibility that insomnia and nostalgia might be viewed as bearers of important existential information (cf. sociologist of religion Peter L. Berger and his concept of “signals of transcendence”).
Prognostic factors in radiotherapy of anaplastic thyroid carcinoma: a single center study over 31 years
Authors: Jacob Julia , Vordermark Dirk , Lorenz Kerstin , Medenwald Daniel 
Published: April 2023

Abstract
Background
Anaplastic thyroid carcinoma has a very poor prognosis. We analyzed the effect of surgery, radiotherapy and chemotherapy on survival time and side effects in patients with ATC.

Methods
We retrospectively analyzed all patients (n = 63) with histologically confirmed ATC who presented at our clinic between 1989 and 2020. We analyzed the survival with Kaplan–Meier curves and cox proportional hazard models and acute toxicities with logistic regression models.

Results
Out of 63 patients, 62 received radiotherapy, 74% underwent surgery and 24% received combined chemotherapy. A median radiation dose of 49 Gy (range 4–66 Gy) was applied. In 32% of the cases opposing-field technique was used, in 18% 3D-conformal, in 27% a combination of opposing field and 3D-conformal technique and 21% obtained IMRT (intensity modulated radiotherapy) or VMAT (volumetric modulated arc radiotherapy). Median overall survival (OS) was 6 months. We identified five predictive factors relevant for survival: absence of distant metastases at the time of diagnosis (OS 8 months), surgery (OS 9.8 months), resection status R0 (OS 14 months), radiation dose of 50 Gy or higher (OS 13 months) and multimodal therapy (surgery, radiotherapy and chemotherapy) with a median OS of 9.7 months.

Conclusion
In spite of the dismal outcome, longer survival can be achieved in some patients with ATC using surgery and radiotherapy with a high radiation dose. Compared to our previous study, there are no significant advantages in overall survival.
Trial registration Retrospectively registered.
Randomized controlled trial data for successful new drug application for rare diseases in the United States
Authors: Kubota Yosuke , Narukawa Mamoru 
Published: April 2023

Abstract
Background
Randomized controlled trial (RCT) data have important implications in drug development. However, the feasibility and cost of conducting RCTs lower the motivation for drug development, especially for rare diseases. We investigated the potential factors associated with the need for RCTs in the clinical data package for new drug applications for rare diseases in the United States (US). This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications.

Results
Multivariable logistic regression analysis showed that the severity of the disease outcome (odds ratio [OR] 5.63, 95% confidence interval [CI] 2.64–12.00), type of drug usage (odds ratio [OR] 2.95, 95% confidence interval [CI] 1.80–18.57), and type of primary endpoint (OR 5.57, 95% CI 2.57–12.06) were associated with the presence or absence of RCTs.

Conclusions
Our results indicated that the presence or absence of RCT data in the clinical data package for successful new drug application in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. These results highlight the importance of selecting target diseases and potential efficacy variables to optimize orphan drug development.
Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy
Authors: Talebi Ali , de Laat Vincent , Spotbeen Xander , Dehairs Jonas , Rambow Florian , Rogiers Aljosja , Vanderhoydonc Frank , Rizotto Lara , Planque Mélanie , Doglioni Ginevra , Motamedi Sahar , Nittner David , Roskams Tania , Agostinis Patrizia , Bechter Oliver , Boecxstaens Veerle , Garmyn Marjan , O’Farrell Marie , Wagman Alan , Kemble George , Leucci Eleonora , Fendt Sarah-Maria , Marine Jean-Christophe , Swinnen Johannes V. 
Published: April 2023

Abstract
Background
One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance.

Methods
Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity.

Results
We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity.

Conclusions
We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.
Investigating the role of AA9 LPMOs in enzymatic hydrolysis of differentially steam-pretreated spruce
Authors: Caputo Fabio , Tõlgo Monika , Naidjonoka Polina , Krogh Kristian B. R. M. , Novy Vera , Olsson Lisbeth 
Published: April 2023

Abstract
Background
To realize the full potential of softwood-based forest biorefineries, the bottlenecks of enzymatic saccharification of softwood need to be better understood. Here, we investigated the potential of lytic polysaccharide monooxygenases (LPMO9s) in softwood saccharification. Norway spruce was steam-pretreated at three different severities, leading to varying hemicellulose retention, lignin condensation, and cellulose ultrastructure. Hydrolyzability of the three substrates was assessed after pretreatment and after an additional knife-milling step, comparing the efficiency of cellulolytic Celluclast + Novozym 188 and LPMO-containing Cellic CTec2 cocktails. The role of Thermoascus aurantiacus TaLPMO9 in saccharification was assessed through time-course analysis of sugar release and accumulation of oxidized sugars, as well as wide-angle X-ray scattering analysis of cellulose ultrastructural changes.

Results
Glucose yield was 6% (w/w) with the mildest pretreatment (steam pretreatment at 210 °C without catalyst) and 66% (w/w) with the harshest (steam pretreatment at 210 °C with 3%(w/w) SO2) when using Celluclast + Novozym 188. Surprisingly, the yield was lower with all substrates when Cellic CTec2 was used. Therefore, the conditions for optimal LPMO activity were tested and it was found that enough O2 was present over the headspace and that the reducing power of the lignin of all three substrates was sufficient for the LPMOs in Cellic CTec2 to be active. Supplementation of Celluclast + Novozym 188 with TaLPMO9 increased the conversion of glucan by 1.6-fold and xylan by 1.5-fold, which was evident primarily in the later stages of saccharification (24–72 h). Improved glucan conversion could be explained by drastically reduced cellulose crystallinity of spruce substrates upon TaLPMO9 supplementation.

Conclusion
Our study demonstrated that LPMO addition to hydrolytic enzymes improves the release of glucose and xylose from steam-pretreated softwood substrates. Furthermore, softwood lignin provides enough reducing power for LPMOs, irrespective of pretreatment severity. These results provided new insights into the potential role of LPMOs in saccharification of industrially relevant softwood substrates.
Association of 410L, 1016I and 1534C kdr mutations with pyrethroid resistance in Aedes aegypti from Ouagadougou, Burkina Faso, and development of a one-step multiplex PCR method for the simultaneous detection of 1534C and 1016I kdr mutations
Authors: Sombié Aboubacar , Ouédraogo Wendegoudi Mathias , Oté Manabu , Saiki Erisha , Sakurai Tatsuya , Yaméogo Félix , Sanon Antoine , McCall Philip J. , Kanuka Hirotaka , Weetman David , Badolo Athanase 
Published: April 2023

Abstract
Background
Since 2000, Burkina Faso has experienced regular dengue cases and outbreaks, making dengue an increasingly important health concern for the country. Previous studies in Burkina Faso reported that resistance of Aedes aegypti to pyrethroid insecticides was associated with the F1534C and V1016I kdr mutations. The current study reports high resistance of Ae. aegypti populations to pyrethroid insecticides, likely supported by mutations in the voltage-gated sodium channel, here evidenced by genotyping the kdr SNPs V410L, V1016I and F1534C. We also describe a new multiplex PCR-based diagnostic of F1534C and V1016I kdr SNPs.

Methods
Larvae of Ae. aegypti were collected from three health districts of Ouagadougou in 2018. The resistance status of Ae. aegypti to permethrin (15 μg/ml) and deltamethrin (10 μg/ml) was tested using bottles and to malathion (5%) using WHO tube tests. All bioassays used 1-h exposure and mortality recorded 24 h post-exposure. Bioassay results were interpreted according to WHO thresholds for resistance diagnosis. The kdr mutations were screened using AS-PCR and TaqMan methods in exposed and non-exposed Aedes mosquitoes.

Results
Females from all health districts were resistant to permethrin and deltamethrin (< 20% mortality) but were fully susceptible to 5% malathion. The F1534C and V1016I kdr mutations were successfully detected using a newly developed multiplex PCR in perfect agreement with TaqMan method. The 1534C/1016I/410L haplotype was correlated with permethrin resistance but not with deltamethrin resistance; however, the test power was limited by a low frequency of dead individuals in deltamethrin exposure.

Conclusions
Resistance to pyrethroid insecticides is associated with kdr mutant haplotypes, while the absence of substantial resistance to malathion suggests that it remains a viable option for dengue vector control in Ouagadougou.
Identification of gametocyte-associated pir genes in the rodent malaria parasite, Plasmodium chabaudi chabaudi AS
Authors: Cunningham Deirdre A. , Reid Adam J. , Hosking Caroline , Deroost Katrien , Tumwine-Downey Irene , Sanders Mandy , Langhorne Jean 
Published: April 2023

Abstract
Objective
To analyse the transcriptional profiles of the pir multigene family of Plasmodium chabaudi chabaudi in male and female gametocytes isolated from the blood of infected mice.

Results
Infected red blood cells containing female and male P. chabaudi gametocytes transcribe a distinct set of genes encoded by the multigene family pir. The overall patterns are similar to what has been observed in the close relative P. berghei, but here we show that gametocyte-associated pir genes are distinct from those involved in chronic blood-stage infection and highlight a male-associated pir gene which should be the focus of future studies.
The embryology, metamorphosis, and muscle development of Schizocardium karankawa sp. nov. (Enteropneusta) from the Gulf of Mexico
Authors: Jabr Noura , Gonzalez Paul , Kocot Kevin M. , Cameron Christopher B. 
Published: April 2023

AbstractSchizocardium karankawa sp. nov. has been collected from subtidal muds of the Laguna Madre, Texas, and the Mississippi coast, Gulf of Mexico. The Texas population is reproductive from early February to mid-April. Gametes are liberated by a small incision in a gonad. Oocyte germinal vesicle breakdown is increased in the presence of sperm, and the highest fertilization success was in the artificial seawater Jamarin U. Manually dechorionated embryos develop normally. Development was asynchronous via a tornaria larva, metamorphosis and maintained to the juvenile worm 6 gill-pore stage. Phalloidin-labeled late-stage tornaria revealed retractor muscles that connect the pericardial sac with the apical tuft anteriorly, the oesophagus ventrally, and muscle cells of the early mesocoels. The muscle development of early juvenile worms began with dorso-lateral trunk muscles, lateral trunk bands, and sphincters around the gill pores and anus. Adult worms are characterized by a stomochord that bifurcates anteriorly into paired vermiform processes, gill bars that extend almost the entire dorsal to ventral branchial region resulting in a narrow ventral hypobranchial ridge, and an elaborate epibranchial organ with six zones of discrete cell types. The trunk has up to three rows of liver sacs, and lateral gonads. The acorn worm evo-devo model species Saccoglossus kowalevskii, Ptychodera flava, and Schizocardium californicum are phylogenetically distant with disparate life histories. S. karnakawa from S. californicum are phylogenetically close, and differences between them that become apparent as adult worms include the number of gill pores and hepatic sacs, and elaborations of the heart–kidney–stomochord complex. An important challenge for evolutionary developmental biology is to form links from phylogenetically distant and large-scale differences to phylogenetically close and small-scale differences. This description of the embryology, development, and adult morphology of S. karankawa permits investigations into how acorn worm development evolves at fine scales.
Silencing NTPDase3 activity rehabilitates the osteogenic commitment of post-menopausal stem cell bone progenitors
Authors: Noronha-Matos José Bernardo , Pinto-Cardoso Rui , Bessa-Andrês Catarina , Magalhães-Cardoso Maria Teresa , Ferreirinha Fátima , Costa Maria Adelina , Marinhas José , Freitas Rolando , Lemos Rui , Vilaça Adélio , Oliveira António , Pelletier Julie , Sévigny Jean , Correia-de-Sá Paulo 
Published: April 2023

Abstract
Background
Endogenously released adenine and uracil nucleotides favour the osteogenic commitment of bone marrow-derived mesenchymal stromal cells (BM-MSCs) through the activation of ATP-sensitive P2X7 and UDP-sensitive P2Y6 receptors. Yet, these nucleotides have their osteogenic potential compromised in post-menopausal (Pm) women due to overexpression of nucleotide metabolizing enzymes, namely NTPDase3. This prompted us to investigate whether NTPDase3 gene silencing or inhibition of its enzymatic activity could rehabilitate the osteogenic potential of Pm BM-MSCs.

Methods
MSCs were harvested from the bone marrow of Pm women (69 ± 2 years old) and younger female controls (22 ± 4 years old). The cells were allowed to grow for 35 days in an osteogenic-inducing medium in either the absence or the presence of NTPDase3 inhibitors (PSB 06126 and hN3-B3s antibody); pre-treatment with a lentiviral short hairpin RNA (Lenti-shRNA) was used to silence the NTPDase3 gene expression. Immunofluorescence confocal microscopy was used to monitor protein cell densities. The osteogenic commitment of BM-MSCs was assessed by increases in the alkaline phosphatase (ALP) activity. The amount of the osteogenic transcription factor Osterix and the alizarin red-stained bone nodule formation. ATP was measured with the luciferin-luciferase bioluminescence assay. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC

Results
The extracellular catabolism of ATP and UDP was faster in BM-MSCs from Pm women compared to younger females. The immunoreactivity against NTPDase3 increased 5.6-fold in BM-MSCs from Pm women vs. younger females. Selective inhibition or transient NTPDase3 gene silencing increased the extracellular accumulation of adenine and uracil nucleotides in cultured Pm BM-MSCs. Downregulation of NTPDase3 expression or activity rehabilitated the osteogenic commitment of Pm BM-MSCs measured as increases in ALP activity, Osterix protein cellular content and bone nodule formation; blockage of P2X7 and P2Y6 purinoceptors prevented this effect.

Conclusions
Data suggest that NTPDase3 overexpression in BM-MSCs may be a clinical surrogate of the osteogenic differentiation impairment in Pm women. Thus, besides P2X7 and P2Y6 receptors activation, targeting NTPDase3 may represent a novel therapeutic strategy to increase bone mass and reduce the osteoporotic risk of fractures in Pm women.