bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic association of circulating interleukins and risk of colorectal cancer: A bidirectional Mendelian randomization study
Authors: Dong Jiaxing , Jiang Wanju , Zhang Wenjia , Hu Renhao , Huang Zhiye , Guo Taohua , Du Tao , Jiang Xiaohua
Published: January 2024

Background

Previous studies have reported that inflammation, especially interleukin family members, plays an important role in the development of colorectal cancer (CRC). However, because of various confounders and the lack of clinical randomized controlled trial, the causal relationship between genetically predicted level of interleukin family and CRC risk has not been fully explained.

Objective

Bi‐directional Mendelian randomization (MR) was conducted to investigate the causal association between interleukin family members and CRC.

Methods

Several genetic variables were extracted as instrumental variables (IVs) from summary data of genome‐wide association studies (GWAS) for interleukin and CRC. IVs of interleukin family were obtained from recently published GWAS studies and the summary data of CRC was from FinnGen Biobank. After a series of quality control measures and strict screening, six models were used to evaluate the causal relationship. Pleiotropy, heterogeneity test, and a variety of sensitivity analysis were also used to estimate the robustness of the model results.

Results

Genetically predicted higher circulating levels of IL‐2 (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.63–0.92; p = .0043), IL‐17F(OR: 0.78; 95% CI: 0.62–1.00; p = .015), and IL‐31 (OR: 0.88; 95% CI: 0.79–0.98; p = .023) were suggestively associated with decreased CRC risk. However, higher level of IL‐10 (OR: 1.40; 95% CI: 1.18–1.65; p = .000094) was causally associated with increased risk of CRC. Reverse MR results indicated that the exposure of CRC was suggestively associated with higher levels of IL‐36α (OR: 1.23; 95% CI: 1.01–1.49; p = .040) and IL‐17RD (OR: 1.22; 95% CI, 1.00–1.48; p = .048) and lower level of IL‐13 (OR: 0.78; 95% CI: 0.65–0.95; p = .013). The overall MR results did not provide evidence for causal relationships between other interleukins and CRC (p > .05).

Conclusion

We offer suggestive evidence supporting a potential causal relationship between circulating interleukins and CRC, underscoring the significance of targeting circulating interleukins as a strategy to mitigate the incidence of CRC.
Genome‐wide SNP discovery and genotyping delineates potential QTLs underlying major yield‐attributing traits in buckwheat
Authors: Naik Samiullah , Sudan Jebi , Urwat Uneeb , Pakhtoon Mohammad Maqbool , Bhat Basharat , Sharma Varun , Sofi Parvaze A. , Shikari Asif B. , Bhat Bilal A. , Sofi Najeebul Rehman , Prasad P. V. Vara , Zargar Sajad Majeed
Published: January 2024

Buckwheat (Fagopyrum spp.) is an important nutritional and nutraceutical‐rich pseudo‐cereal crop. Despite its obvious potential as a functional food, buckwheat has not been fully harnessed due to its low yield, self‐incompatibility, increased seed cracking, limited seed set, lodging, and frost susceptibility. The inadequate availability of genomics resources in buckwheat is one of the major reasons for this. In the present study, genome‐wide association mapping (GWAS) was conducted to identify loci associated with various morphological and yield‐related traits in buckwheat. High throughput genotyping by sequencing led to the identification of 34,978 single nucleotide polymorphisms that were distributed across eight chromosomes. Population structure analysis grouped the genotypes into three sub‐populations. The genotypes were also characterized for various qualitative and quantitative traits at two diverse locations, the analysis of which revealed a significant difference in the mean values. The association analysis revealed a total of 71 significant marker–trait associations across eight chromosomes. The candidate genes were identified near 100 Kb of quantitative trait loci (QTLs), providing insights into several metabolic and biosynthetic pathways. The integration of phenology and GWAS in the present study is useful to uncover the consistent genomic regions, related markers associated with various yield‐related traits, and potential candidate genes having implications for being utilized in molecular breeding for the improvement of economically important traits in buckwheat. Moreover, the identified QTLs will assist in tracking the desirable alleles of target genes within the buckwheat breeding populations/germplasm.
Uses and Misuses of Commercial Reading Assessment: An Applied Framework for Decision Making in Grades K through 6
Authors: Truckenmiller Adrea J. , Cho Eunsoo , Bourgeois Samantha , Friedman Ellie
Published: January 2024

The purpose of this article was to offer guidance to educators in evaluating the strengths, weaknesses, and most effective uses of commercial reading assessment suites. We provide three resources to help educators who are responsible for making instructional decisions in reading using formal screening, benchmark, interim, and progress‐monitoring assessment suites. First, we recommend a framework for how one can judiciously select and use reading assessment. Then we identify a few common misuses of reading assessment scores and ways to reframe them into more effective uses. Finally, we detail the specific strengths and limitations of six commercial assessment suites commonly used in elementary schools for screening and other specific instructional decisions. The framework we describe could also generalize to other subject matter, grade levels, and types of assessment scores.
Assessment of technological developments for camera‐traps: a wireless transmission system and solar panels
Authors: Barros Ana Luísa , Alcobia Sandra , Gonçalves Paula , MacKenzie Darryl I. , Santos‐Reis Margarida
Published: January 2024

Camera‐trapping is considered a cost‐efficient method to monitor wildlife, but relevant performance constraints remain. We assessed performance and cost‐benefit for 2 recent technological innovations: (i) a wireless transmission system where cameras communicate in a network, and (ii) using solar panels as a camera's sole power supply. The maximum distance between cameras that ensured wireless connection varied between 2 km in open habitats and 335 m in forest habitats with dense tree cover. The cost of using the wireless transmission system was lower for surveys run for >45 days and for >15 sampling units (i.e., camera‐trap sites). For surveys longer than 15 days, using the wireless transmission system required, on average, 8 fewer days of fieldwork. We measured the performance of the solar panels in terms of capture probability, and the solar‐powered cameras (β = −0.015 ± 0.01 in the log scale) outperformed battery‐powered cameras (β = −0.103 ± 0.005) as capture rate decreased more slowly, particularly for nighttime events (difference in capture probability of the solar‐powered relative to the battery‐powered cameras at night, β = 0.09 ± 0.01). We consider that, although camera‐traps with wireless transmission can provide a return on investment for a wide range of survey designs, the constraints on maximum distance for transmission are a limitation. Despite the higher cost, we recommend solar‐powered camera‐traps as they had improved performance with a higher proportion of species events captured than by battery‐powered cameras.
Numerical simulations of entropy generation and Arrhenius activation energy on peristaltic transport of Prandtl‐Eyring fluid in a curved conduit
Authors: Zahir Hina , Muhammad Khursheed , Ali Fizza , Ghazwani Hassan Ali , Hussien Mohamed
Published: January 2024

The study aims to explore the combined impact of activation energy and entropy generation on Prandtl‐Eyring fluid flow within a curved channel, considering Hall and ion slip effects, alongside the influence of nonlinear thermal radiation on heat transfer. This research is pivotal as it delves into the multifaceted relationship among these factors, offering important implications spanning various fields, from engineering to physics. Notably, the findings highlight that heightened nonlinear thermal radiation does not solely elevate entropy generation but also amplifies the Bejan number, signifying a substantial effect on fluid flow dynamics. Furthermore, the investigation reveals an intriguing correlation: lower concentrations paired with higher Arrhenius activation energy values correspond to heightened chemical reaction rates, presenting valuable insights applicable to reaction engineering and material sciences. Additionally, exploring the impact of activation energy and entropy generation within this fluid model presents a unique approach to understanding complex fluid dynamics and heat transfer phenomena, offering insights crucial for various engineering applications, particularly in fluid dynamics, thermal sciences, and materials engineering.
Gauge boson mass dependence and chiral anomalies in generalized massless Schwinger models
Authors: Georgi Howard
Published: January 2024

Abstract

I bosonize the position-space correlators of flavor-diagonal scalar fermion bilinears in arbitrary generalizations of the Schwinger model with nF massless fermions coupled to nA gauge bosons for nF ≥ nA. For nA = nF, the fermion bilinears can be bosonized in terms of nF scalars with masses proportional to the gauge couplings. As in the Schwinger model, bosonization can be used to find all correlators, including those that are forbidden in perturbation theory by anomalous chiral symmetries, but there are subtleties when there is more than one gauge boson. The new result here is the general treatment of the dependence on gauge boson masses in models with more than one gauge symmetry. For nA < nF, there are fermion bilinears with nontrivial anomalous dimensions and there are unbroken chiral symmetries so some correlators vanish while others are non-zero due to chiral anomlies. Taking careful account of the dependence on the masses, I show how the nA < nF models emerge from nA = nF as gauge couplings (and thus gauge boson masses) go to zero. When this is done properly, the limit of zero gauge coupling is smooth. Our consistent treatment of gauge boson masses guarantees that anomalous symmetries are broken while unbroken chiral symmetries are preserved because correlators that break the non-anomalous symmetries go to zero in the limit of zero gauge coupling.
Gesundheit und Klimawandel – welche Potenziale haben versorgungsnahe Daten?
Authors: Günster Christian , Schmuker Caroline
Published: January 2024

Dieser Beitrag geht der Frage nach, welche Auswirkungen der Klimawandel auf die Gesundheit haben kann und inwieweit versorgungsnahe Daten zur Forschung in diesem Themenfeld beitragen können. Der Klimawandel verändert die Umwelt- und Lebensbedingungen der Menschheit, er ist damit auch zu einem relevanten Gesundheitsproblem geworden. Die Zunahme von Extremwetterereignissen, Veränderungen bei der UV- und Luftschadstoffbelastung sowie die klimaassoziierte Verbreitung von Allergenen oder neuartigen Erregern verändern das Spektrum an Erkrankungen und den medizinischen Versorgungsbedarf in der Bevölkerung erheblich. Allerdings liegen bislang nur wenige Erkenntnisse zu den Folgen für das Gesundheitssystem und zu besonders betroffenen Bevölkerungsgruppen in Deutschland vor. Versorgungsnahe Daten (Primärdaten, Registerdaten, Sekundärdaten) in Verbindung mit Umweltexpositionsdaten und modulierenden Daten (z. B. sozioökonomische Daten) haben das Potenzial, die Forschung zu den gesundheitlichen Folgen des Klimawandels erheblich voranzubringen. Dieser Beitrag benennt die Veränderungen der Umwelt- und Lebensbedingungen sowie der damit verbundenen gesundheitlichen Risiken. Er beschreibt die Datengrundlagen, die grundsätzlich zur Analyse gesundheitlicher Auswirkungen des Klimawandels zur Verfügung stehen. An einem konkreten Beispiel wird aufgezeigt, wie die Zusammenführung von individuellen Gesundheitsdaten (hier GKV-Abrechnungsdaten), Umweltexpositionsdaten und modulierenden Daten gelingen kann. Der Beitrag bietet abschließend eine umfassende Übersicht über offene Forschungsfragen, die mit versorgungsnahen Daten beantwortet werden können.
Unklare Minderung des Allgemeinzustandes bei Patientin mit Lungenkarzinom
Authors: Brägelmann J. , Becker S. , Stenzel D. , Budahn A.
Published: January 2024

Eine 63-jährige Patientin mit Lungenkarzinom stellte sich erstmalig in unserer Notaufnahme mit plötzlicher Reduktion des Allgemeinzustands, Erbrechen und ausgeprägter Schwäche vor. Sie gab an, aufgrund des Lungenkarzinoms eine Chemotherapie zu erhalten, und verneinte weitere, relevante Vorerkrankungen. Unsere initiale Verdachtsdiagnose waren eine zytostatikainduzierte Nausea und Emesis. Die in der Notaufnahme durchgeführte Diagnostik erbrachte entgegen dieser Verdachtsdiagnose die Befunde einer Ketoazidose auf dem Boden einer Erstmanifestation eines Diabetes mellitus mit hyperglykämischer Entgleisung sowie einer schweren, manifesten Hypothyreose. Nach Beschaffung der Vorbefunde wurde evident, dass die Patientin keine Chemotherapie, sondern eine Immuncheckpointtherapie mittels Durvalumab erhielt. Die beschriebenen Erstmanifestationen waren demzufolge als durvalumabassoziierte Immunreaktionen zu werten. Nach Einleitung einer diabetischen Rekompensationstherapie und Substitution mittels L‑Thyroxin konnte eine rasche Verbesserung des Allgemeinzustands erreicht werden. Wären für uns relevante Vorbefunde schon zu Behandlungsbeginn abrufbar gewesen, beispielsweise durch die elektronische Patientenakte, wären die korrekte Interpretation der Symptome und die korrekte Therapie früher möglich gewesen.
Genome-wide association analysis identifies a consistent QTL for powdery mildew resistance on chromosome 3A in Nordic and Baltic spring wheat
Authors: Lin Min , Islamov Bulat , Aleliūnas Andrius , Armonienė Rita , Gorash Andrii , Meigas Egon , Ingver Anne , Tamm Ilmar , Kollist Hannes , Strazdiņa Vija , Bleidere Māra , Brazauskas Gintaras , Lillemo Morten
Published: January 2024

Key message

QPm.NOBAL-3A is an important QTL providing robust adult plant powdery mildew resistance in Nordic and Baltic spring wheat, aiding sustainable crop protection and breeding.

Powdery mildew, caused by the biotrophic fungal pathogen Blumeria graminis f. sp. tritici, poses a significant threat to bread wheat (Triticum aestivum L.), one of the world’s most crucial cereal crops. Enhancing cultivar resistance against this devastating disease requires a comprehensive understanding of the genetic basis of powdery mildew resistance. In this study, we performed a genome-wide association study (GWAS) using extensive field trial data from multiple environments across Estonia, Latvia, Lithuania, and Norway. The study involved a diverse panel of recent wheat cultivars and breeding lines sourced from the Baltic region and Norway. We identified a major quantitative trait locus (QTL) on chromosome 3A, designated as QPm.NOBAL-3A, which consistently conferred high resistance to powdery mildew across various environments and countries. Furthermore, the consistency of the QTL haplotype effect was validated using an independent Norwegian spring wheat panel. Subsequent greenhouse seedling inoculations with 15 representative powdery mildew isolates on a subset of the GWAS panel indicated that this QTL provides adult plant resistance and is likely of race non-specific nature. Moreover, we developed and validated KASP markers for QPm.NOBAL-3A tailored for use in breeding. These findings provide a critical foundation for marker-assisted selection in breeding programs aimed at pyramiding resistance QTL/genes to achieve durable and broad-spectrum resistance against powdery mildew.
Solving quasimonotone and non-monotone variational inequalities
Authors: Uzor V. A. , Alakoya T. O. , Mewomo O. T. , Gibali A.
Published: January 2024

We present a simple iterative method for solving quasimonotone as well as classical variational inequalities without monotonicity. Strong convergence analysis is given under mild conditions and thus generalize the few existing results that only present weak convergence methods under restrictive assumptions. We give finite and infinite dimensional numerical examples to compare and illustrate the simplicity and computational advantages of the proposed scheme.
Molecular mechanism of anticancer effect of heat shock protein 90 inhibitor BIIB021 in human bladder cancer cell line
Authors: Asdemir Aydemir , Özgür Aykut
Published: January 2024

Bladder cancer is a type of urologic malignancy that exhibits significant morbidity, mortality, and treatment costs. Inhibition of heat shock protein 90 (HSP90) activity has been a promising pharmacological strategy for blocking of bladder cancer pathogenesis. BIIB021 is a next-generation HSP90 inhibitor which interrupts ATP hydrolysis process of HSP90 and inhibits the stabilization and correct folding of client proteins. In current study, we aimed to investigate the molecular mechanism of the anticancer activity of BIIB021 in human bladder cancer T24 cells. Our results revealed that nanomolar concentration of BIIB021 decreased viability of T24 cell. BIIB021 downregulated HSP90 expression in T24 cells and inhibited the refolding activity of luciferase in the presence of T24 cell lysate. PCR array data indicated a significant alteration in transcript levels of cancer-related genes involved in metastases, apoptotic cell death, cell cycle, cellular senescence, DNA damage and repair mechanisms, epithelial-to-mesenchymal transition, hypoxia, telomeres and telomerase, and cancer metabolism pathways in T24 cells. All findings hypothesize that BIIB021 could exhibit as effective HSP90 inhibitor in the future for treatment of bladder cancer patients.
Multiplexed electrochemical liposomes applied to the detection of nucleic acids for Influenza A, Influenza B and SARS-CoV-2
Authors: Gerstl Florian , Loessl Michael , Borggraefe Veronika , Baeumner Antje J.
Published: January 2024

Multiplexing is a relevant strategy for biosensors to improve accuracy and decision-making due to the increased amount of simultaneously obtained information. Liposomes offer unique benefits for label-based multiplexing since a variety of different marker molecules can be encapsulated, leading to intrinsic signal amplification and enabling a variety of detection formats. We successfully developed an electrochemical (EC) liposome-based platform technology for the simultaneous detection of at least three analytes by studying parameters to ensure specific and sensitive bioassay performance. Influenza A and B and SARS-CoV-2 sequences served as model system in a standard sandwich hybridization assay. Studies included encapsulants, probe distribution on liposomes and capture beads, assay setup and interferences between liposomes to also ensure a generalization of the platform. Ruthenium hexamine(III), potassium hexacyanoferrate(II) and m-carboxy luminol, when encapsulated separately into a liposome, provided desirable long-term stability of at least 12 months and no cross-signals between liposomes. Through the optimization process, low limits of detections of 1.6 nmol L−1, 125 pmol L−1 and 130 pmol L−1, respectively, were achieved in a multiplexed assay setup, which were similar to singleplex assays. Non-specific interactions were limited to 25.1%, 7.6% and 7.5%, respectively, through sequential liposome incubations and singleplex capture bead designs. Here, ruthenium hexamine liposomes had only mediocre performance so that low overall signal strength translated into higher LODs and worse specificity. A different marker such as ferroin may be an option in the future. The identification of further electrochemical markers will provide new opportunities for liposomes to function as multiplex, orthogonal or internal standard labels in electrochemical bioassays.

Graphical Abstract
Dissipation in Onsager’s Critical Classes and Energy Conservation in $$BV\cap L^\infty $$ with and Without Boundary
Authors: De Rosa Luigi , Inversi Marco
Published: January 2024

This paper is concerned with the incompressible Euler equations. In Onsager’s critical classes we provide explicit formulas for the Duchon–Robert measure in terms of the regularization kernel and a family of vector-valued measures$$\{\mu _z\}_z\subset {\mathcal {M}}_{x,t}$${μz}z⊂Mx,t, having some Hölder regularity with respect to the direction$$z\in B_1$$z∈B1. Then, we prove energy conservation for$$L^\infty _{x,t}\cap L^1_t BV_x$$Lx,t∞∩Lt1BVxsolutions, in both the absence or presence of a physical boundary. This result generalises the previously known case of Vortex Sheets, showing that energy conservation follows from the structure of$$L^\infty \cap BV$$L∞∩BVincompressible vector fields rather than the flow having “organized singularities”. The interior energy conservation features the use of Ambrosio’s anisotropic optimization of the convolution kernel and it differs from the usual energy conservation arguments by heavily relying on the incompressibility of the vector field. This is the first energy conservation proof, for a given class of solutions, which fails to simultaneously apply to both compressible and incompressible models, coherently with compressible shocks having non-trivial entropy production. To run the boundary analysis we introduce a notion of “normal Lebesgue trace” for general vector fields, very reminiscent of the one forBVfunctions. We show that having such a null normal trace is basically equivalent to have vanishing boundary energy flux. This goes beyond the previous approaches, laying down a setup which applies to every Lipschitz bounded domain. Allowing any Lipschitz boundary introduces several technicalities to the proof, with a quite geometrical/measure-theoretical flavour.
Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? A Systematic Review of the Literature
Authors: Verdonk Sara J. E. , Storoni Silvia , Micha Dimitra , van den Aardweg Joost G. , Versacci Paolo , Celli Luca , de Vries Ralph , Zhytnik Lidiia , Kamp Otto , Bugiani Marianna , Eekhoff Elisabeth M. W.
Published: January 2024

Osteogenesis imperfecta (OI) is a rare genetic disorder caused by abnormal collagen type I production. While OI is primarily characterized by bone fragility and deformities, patients also have extraskeletal manifestations, including an increased risk of cardiovascular disease. This review provides a comprehensive overview of the literature on cardiovascular diseases in OI patients in order to raise awareness of this understudied clinical aspect of OI and support clinical guidelines. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, Web of Science and Scopus was conducted that included articles from the inception of these databases to April 2023. Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI than in control individuals. Moreover, a larger aortic root was observed in OI compared to controls. Various cardiovascular diseases appear to be more prevalent in OI than in controls. These cardiovascular abnormalities are observed in all types of OI and at all ages, including young children. As there are insufficient longitudinal studies, it is unknown whether these abnormalities are progressive in nature in OI patients. Based on these findings, we would recommend referring individuals with OI to a cardiologist with a low-threshold.
Towards validation in clinical routine: a comparative analysis of visual MTA ratings versus the automated ratio between inferior lateral ventricle and hippocampal volumes in Alzheimer’s disease diagnosis
Authors: Wittens Mandy M. J. , Allemeersch Gert-Jan , Sima Diana M. , Vanderhasselt Tim , Raeymaeckers Steven , Fransen Erik , Smeets Dirk , de Mey Johan , Bjerke Maria , Engelborghs Sebastiaan
Published: January 2024

Purpose

To assess the performance of the inferior lateral ventricle (ILV) to hippocampal (Hip) volume ratio on brain MRI, for Alzheimer’s disease (AD) diagnostics, comparing it to individual automated ILV and hippocampal volumes, and visual medial temporal lobe atrophy (MTA) consensus ratings.

Methods

One-hundred-twelve subjects (mean age ± SD, 66.85 ± 13.64 years) with varying degrees of cognitive decline underwent MRI using a Philips Ingenia 3T. The MTA scale by Scheltens, rated on coronal 3D T1-weighted images, was determined by three experienced radiologists, blinded to diagnosis and sex. Automated volumetry was computed by icobrain dm (v. 5.10) for total, left, right hippocampal, and ILV volumes. The ILV/Hip ratio, defined as the percentage ratio between ILV and hippocampal volumes, was calculated and compared against a normative reference population (n = 1903). Inter-rater agreement, association, classification accuracy, and clinical interpretability on patient level were reported.

Results

Visual MTA scores showed excellent inter-rater agreement. Ordinal logistic regression and correlation analyses demonstrated robust associations between automated brain segmentations and visual MTA ratings, with the ILV/Hip ratio consistently outperforming individual hippocampal and ILV volumes. Pairwise classification accuracy showed good performance without statistically significant differences between the ILV/Hip ratio and visual MTA across disease stages, indicating potential interchangeability. Comparison to the normative population and clinical interpretability assessments showed commensurability in classifying MTA “severity” between visual MTA and ILV/Hip ratio measurements.

Conclusion

The ILV/Hip ratio shows the highest correlation to visual MTA, in comparison to automated individual ILV and hippocampal volumes, offering standardized measures for diagnostic support in different stages of cognitive decline.
Establishing a High-Quality Pediatric Cardiac Surgery Program in Post-Conflict Regions: A Model for Limited Resource Countries
Authors: Youssef Tammam , Bitar Fouad , Alogla Hassanain , El Khoury Maya , Moukhaiber Jihan , Alamin Farah , AlHareth Bassam , Gabriel Cristoveanu Catalin , Youssef Rana , Abouzahr Labib , Abdul Sater Zahi , Bitar Fadi
Published: January 2024

Background

Congenital Heart Disease stands as a prominent cause of infant mortality, with notable disparities in surgical outcomes evident between high-income and low- to middle-income countries.

Objective

This study presents a collaborative partnership between a local governmental entity and an international private organization to establish a high-quality Pediatric Cardiac Surgery Program in a post-conflict limited resource country, Iraq.

Methods

A descriptive retrospective study analyzed pediatric cardiac surgery procedures performed by a visiting pediatric heart surgery team from October 2021 to October 2022, funded by the Ministry of Health (MOH). We used the STS-EACTS complexity scoring model (STAT) to assess mortality risks associated with surgical procedures.

Results

A total of 144 patients underwent 148 procedures. Infants comprised 58.3% of the patients. The most common anomalies included tetralogy of Fallot, ventricular septal defect, and various single ventricle categories, constituting 76% of the patient cohort. The overall surgical mortality rate was 4.1%, with an observed/expected surgical mortality rate of 1.1 (95% CI 0.5, 2.3). There was no significant difference between our observed surgical mortality in Category 2, 3, and 4 and those expected/reported by the STS-EACTS Database (p = 0.07, p = 0.72, and p = 0.12, respectively). The expenses incurred by the MOH for conducting surgeries in Iraq were lower than the alternative of sending patients abroad for the same procedures.

Conclusion

The partnership model between a local public entity committed to infrastructure development and funding and an international private organization delivering clinical and training services can provide the foundation for building sustainable, high-quality in situ programs in upper-middle-income countries.
Systemic metabolic engineering of Enterobacter aerogenes for efficient 2,3-butanediol production
Authors: Lu Ping , Bai Ruoxuan , Gao Ting , Chen Jiale , Jiang Ke , Zhu Yalun , Lu Ye , Zhang Shuting , Xu Fangxu , Zhao Hongxin
Published: January 2024

2,3-Butanediol (2,3-BDO) is an important gateway molecule for many chemical derivatives. Currently, microbial production is gradually being recognized as a green and sustainable alternative to petrochemical synthesis, but the titer, yield, and productivity of microbial 2,3-BDO remain suboptimal. Here, we used systemic metabolic engineering strategies to debottleneck the 2,3-BDO production in Enterobacter aerogenes. Firstly, the pyruvate metabolic network was reconstructed by deleting genes for by-product synthesis to improve the flux toward 2,3-BDO synthesis, which resulted in a 90% increase of the product titer. Secondly, the 2,3-BDO productivity of the IAM1183-LPCT/D was increased by 55% due to the heterologous expression of DR1558 which boosted cell resistance to abiotic stress. Thirdly, carbon sources were optimized to further improve the yield of target products. The IAM1183-LPCT/D showed the highest titer of 2,3-BDO from sucrose, 20% higher than that from glucose, and the yield of 2,3-BDO reached 0.49 g/g. Finally, the titer of 2,3-BDO of IAM1183-LPCT/D in a 5-L fermenter reached 22.93 g/L, 85% higher than the wild-type strain, and the titer of by-products except ethanol was very low.

Key points

Deletion of five key genes in E. aerogenes improved 2,3-BDO production

The titer of 2,3-BDO was increased by 90% by regulating metabolic flux

Response regulator DR1558 was expressed to increase 2,3-BDO productivity

Graphical abstract
Nitrogen balance and supply in Australasian mushroom composts
Authors: Noble Ralph , Thai Meghann , Kertesz Michael A.
Published: January 2024

Mushrooms are an important source of protein in the human diet. They are increasingly viewed as a sustainable meat replacement in an era of growing populations, with button mushrooms (Agaricus bisporus) the most popular and economically important mushroom in Europe, Australia and North America. Button mushrooms are cultivated on a defined, straw-derived compost, and the nitrogen (N) required to grow these high-protein foods is provided mainly by the addition of poultry manure and horse manure. Using the correct balance of carbon (C) and N sources to produce mushroom compost is critically important in achieving maximum mushroom yields. Changes in the amount and form of N added, the rate and timing of N addition and the other compost components used can dramatically change the proportion of added N recovered in the mushroom caps, the yield and quality of the mushrooms and the loss of N as ammonia and nitrogen oxide gases during composting. This review examines how N supply for mushroom production can be optimised by the use of a broad range of inorganic and organic N sources for mushroom composting, together with the use of recycled compost leachate, gypsum and protein-rich supplements. Integrating this knowledge into our current molecular understanding of mushroom compost biology will provide a pathway for the development of sustainable solutions in mushroom production that will contribute strongly to the circular economy.

Key points

• Nitrogen for production of mushroom compost can be provided as a much wider range of organic feedstocks or inorganic compounds than currently used

• Most of the nitrogen used in production of mushroom compost is not recovered as protein in the mushroom crop

• The sustainability of mushroom cropping would be increased through alternative nitrogen management during composting and cropping
New biomarkers underlying acetic acid tolerance in the probiotic yeast Saccharomyces cerevisiae var. boulardii
Authors: Samakkarn Wiwan , Vandecruys Paul , Moreno Maria Remedios Foulquié , Thevelein Johan , Ratanakhanokchai Khanok , Soontorngun Nitnipa
Published: January 2024

Evolutionary engineering experiments, in combination with omics technologies, revealed genetic markers underpinning the molecular mechanisms behind acetic acid stress tolerance in the probiotic yeast Saccharomyces cerevisiae var. boulardii. Here, compared to the ancestral Ent strain, evolved yeast strains could quickly adapt to high acetic acid levels (7 g/L) and displayed a shorter lag phase of growth. Bioinformatic-aided whole-genome sequencing identified genetic changes associated with enhanced strain robustness to acetic acid: a duplicated sequence in the essential endocytotic PAN1 gene, mutations in a cell wall mannoprotein (dan4Thr192del), a lipid and fatty acid transcription factor (oaf1Ser57Pro) and a thiamine biosynthetic enzyme (thi13Thr332Ala). Induction of PAN1 and its associated endocytic complex SLA1 and END3 genes was observed following acetic acid treatment in the evolved-resistant strain when compared to the ancestral strain. Genome-wide transcriptomic analysis of the evolved Ent acid-resistant strain (Ent ev16) also revealed a dramatic rewiring of gene expression among genes associated with cellular transport, metabolism, oxidative stress response, biosynthesis/organization of the cell wall, and cell membrane. Some evolved strains also displayed better growth at high acetic acid concentrations and exhibited adaptive metabolic profiles with altered levels of secreted ethanol (4.0–6.4% decrease), glycerol (31.4–78.5% increase), and acetic acid (53.0–60.3% increase) when compared to the ancestral strain. Overall, duplication/mutations and transcriptional alterations are key mechanisms driving improved acetic acid tolerance in probiotic strains. We successfully used adaptive evolutionary engineering to rapidly and effectively elucidate the molecular mechanisms behind important industrial traits to obtain robust probiotic yeast strains for myriad biotechnological applications.

Key points

•Acetic acid adaptation of evolutionary engineered robust probiotic yeast S. boulardii

•Enterol ev16 with altered genetic and transcriptomic profiles survives in up to 7 g/L acetic acid

•Improved acetic acid tolerance of S. boulardii ev16 with mutated PAN1, DAN4, OAF1, and THI13 genes

Graphical Abstract
Effects of Leishmania major infection on the gut microbiome of resistant and susceptible mice
Authors: Mrázek Jakub , Mrázková Lucie , Mekadim Chahrazed , Jarošíková Taťána , Krayem Imtissal , Sohrabi Yahya , Demant Peter , Lipoldová Marie
Published: January 2024

Cutaneous leishmaniasis, a parasitic disease caused by Leishmania major, is a widely frequent form in humans. To explore the importance of the host gut microbiota and to investigate its changes during L. major infection, two different groups of mouse models were assessed. The microbiome of two parts of the host gut—ileum and colon—from infected and non-infected mice were characterised by sequencing of 16S rDNA using an Ion Torrent PGM platform. Microbiome analysis was performed to reveal changes related to the susceptibility and the genetics of mice strains in two different gut compartments and to compare the results between infected and non-infected mice. The results showed that Leishmania infection affects mainly the ileum microbiota, whereas the colon bacterial community was more stable. Different biomarkers were determined in the gut microbiota of infected resistant mice and infected susceptible mice using LEfSe analysis. Lactobacillaceae was associated with resistance in the colon microbiota of all resistant mice strains infected with L. major. Genes related to xenobiotic biodegradation and metabolism and amino acid metabolism were primarily enriched in the small intestine microbiome of resistant strains, while genes associated with carbohydrate metabolism and glycan biosynthesis and metabolism were most abundant in the gut microbiome of the infected susceptible mice. These results should improve our understanding of host-parasite interaction and provide important insights into the effect of leishmaniasis on the gut microbiota. Also, this study highlights the role of host genetic variation in shaping the diversity and composition of the gut microbiome.

Key points

• Leishmaniasis may affect mainly the ileum microbiota while colon microbiota was more stable.

• Biomarkers related with resistance or susceptibility were determined in the gut microbiota of mice.

• Several pathways were predicted to be upregulated in the gut microbiota of resistant or susceptible mice.

Graphical Abstract
Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3
Authors: Eichholz Thomas , Heubach Florian , Arendt Anne-Marie , Seitz Christian , Brecht Ines B. , Ebinger Martin , Flaadt Tim , Süsskind Daniela , Richter Lisa , Hülsenbeck Isabel , Zerweck Leonie , Göricke Sophia , Paulsen Frank , Dombrowski Frank , Flotho Christian , Schönberger Stefan , Ketteler Petra , Schulte Johannes , Lang Peter
Published: January 2024

Background

GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors.

Methods

The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed.

Results

We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated.

Conclusion

Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.
Phellinus linteus activates Treg cells via FAK to promote M2 macrophage polarization in hepatocellular carcinoma
Authors: Chen Feihua , Gong Mouchun , Weng Dengcheng , Jin Zhaoqing , Han Guofeng , Yang Ziqiang , Han Junjun , Wang Jianjiang
Published: January 2024

Hepatocellular carcinoma (HCC) is the most prevalent malignant tumor worldwide. Within HCC's tumor microenvironment, focal adhesion kinase (FAK) plays a critical role. Regulatory T cells (Treg) modulate the polarization of tumor-associated macrophages , but the relationship between FAK, Treg cells, and macrophages remains underexplored. Phellinus linteus (PL) shows promise as a treatment for HCC due to its pharmacological effects. This study aimed to explore the relationship between FAK and Treg-macrophages and to assess whether PL could exert a protective effect through the FAK process in HCC. Initially, C57BL/6-FAK−/− tumor-bearing mice were utilized to demonstrate that FAK stimulates HCC tumor development. High dosages (200 μM) of FAK and the FAK activator ZINC40099027 led to an increase in Treg (CD4+CD25+) cells, a decrease in M1 macrophages (F4/80+CD16/32+, IL-12, IL-2, iNOS), and an increase in M2 macrophages (F4/80+CD206+, IL-4, IL-10, Arg1, TGF-β1). Additionally, FAK was found to encourage cell proliferation, migration, invasion, and epithelial-mesenchymal transition while inhibiting apoptosis in HepG2 and SMMC7721 cells. These effects were mediated by the PI3K/AKT1/Janus Kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase (p38 MAPK)/Jun N-terminal Kinase (JNK) signaling pathways. Furthermore, PL exhibited a potent antitumor effect in vivo in a dose-dependent manner, reducing FAK, Treg cells, and M2 macrophages, while increasing M1 macrophages. This effect was achieved through the inhibition of the PI3K/AKT/JAK/STAT3, and p38/JNK pathways. Overall, our findings suggest that FAK promotes HCC via Treg cells that polarize macrophages toward the M2 type through specific signaling pathways. PL, acting through FAK, could be a protective therapy against HCC.
Compatible Spanning Circuits and Forbidden Induced Subgraphs
Authors: Guo Zhiwei , Brause Christoph , Geißer Maximilian , Schiermeyer Ingo
Published: January 2024

A compatible spanning circuit in an edge-colored graph G (not necessarily properly) is defined as a closed trail containing all vertices of G in which any two consecutively traversed edges have distinct colors. The existence of extremal compatible spanning circuits (i.e., compatible Hamilton cycles and compatible Euler tours) has been studied extensively. Recently, sufficient conditions for the existence of compatible spanning circuits visiting each vertex at least a specified number of times in specific edge-colored graphs satisfying certain degree conditions have been established. In this paper, we continue the research on sufficient conditions for the existence of such compatible s-panning circuits. We consider edge-colored graphs containing no certain forbidden induced subgraphs. As applications, we also consider the existence of such compatible spanning circuits in edge-colored graphs G with κ(G) ≥ α(G), κ(G) ≥ α(G) − 1 and κ (G) ≥ α(G), respectively. In this context, κ(G), α(G) and κ (G) denote the connectivity, the independence number and the edge connectivity of a graph G, respectively.
Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden
Authors: Bentivenga Giuseppe Mario , Mammana Angela , Baiardi Simone , Rossi Marcello , Ticca Alice , Magliocchetti Franco , Mastrangelo Andrea , Poleggi Anna , Ladogana Anna , Capellari Sabina , Parchi Piero
Published: January 2024

The development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein (αSyn) in cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance in early pathological stages or low Lewy body (LB) pathology load has only been assessed in small cohorts. Moreover, the relationship between SAA kinetic parameters, the number of αSyn brain seeds and the LB pathology burden assessed by immunohistochemistry has never been systematically investigated. We tested 269 antemortem CSF samples and 138 serially diluted brain homogenates from patients with and without neuropathological evidence of LBD in different stages by the αSyn Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. Moreover, we looked for LB pathology by αSyn immunohistochemistry in a consecutive series of 604 Creutzfeldt–Jakob disease (CJD)-affected brains. αSyn CSF RT-QuIC showed 100% sensitivity in detecting LBD in limbic and neocortical stages. The assay sensitivity was significantly lower in patients in early stages (37.5% in Braak 1 and 2, 73.3% in Braak 3) or with focal pathology (50% in amygdala-predominant). The average number of CSF RT-QuIC positive replicates significantly correlated with LBD stage. Brain homogenate RT-QuIC showed higher sensitivity than immunohistochemistry for the detection of misfolded αSyn. In the latter, the kinetic parameter lag phase (time to reach the positive threshold) strongly correlated with the αSyn seed concentration in serial dilution experiments. Finally, incidental LBD prevalence was 8% in the CJD cohort. The present results indicate that (a) CSF RT-QuIC has high specificity and sufficient sensitivity to detect all patients with LB pathology at Braak stages > 3 and most of those at stage 3; (b) brain deposition of misfolded αSyn precedes the formation of LB and Lewy neurites; (c) αSyn SAA provides “quantitative” information regarding the LB pathology burden, with the lag phase and the number of positive replicates being the most promising variables to be used in the clinical setting.
Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2
Authors: Kleefeld Felix , Horvath Rita , Pinal-Fernandez Iago , Mammen Andrew L. , Casal-Dominguez Maria , Hathazi Denisa , Melchert Sarah , Hahn Katrin , Sickmann Albert , Muselmann-Genschow Claudia , Hentschel Andreas , Preuße Corinna , Roos Andreas , Schoser Benedikt , Stenzel Werner
Published: January 2024

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.