bluuebunny/crossref_metadata_2025_split huggingface dataset:
SETDB1 regulates short interspersed nuclear elements and chromatin loop organization in mouse neural precursor cells
Authors: Sun Daijing , Zhu Yueyan , Peng Wenzhu , Zheng Shenghui , Weng Jie , Dong Shulong , Li Jiaqi , Chen Qi , Ge Chuanhui , Liao Liyong , Dong Yuhao , Liu Yun , Meng Weida , Jiang Yan 
Published: July 2024

Abstract
Background
Transposable elements play a critical role in maintaining genome architecture during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a major subtype of transposable elements, are known to harbor binding sites for the CCCTC-binding factor (CTCF) and pivotal in orchestrating chromatin organization. However, the regulatory mechanisms controlling the activity of SINEs in the developing brain remains elusive.

Results
In our study, we conduct a comprehensive genome-wide epigenetic analysis in mouse neural precursor cells using ATAC-seq, ChIP-seq, whole genome bisulfite sequencing, in situ Hi-C, and RNA-seq. Our findings reveal that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-mediated H3K9me3, in conjunction with DNA methylation, restricts chromatin accessibility on a selective subset of SINEs in neural precursor cells. Mechanistically, loss of Setdb1 increases CTCF access to these SINE elements and contributes to chromatin loop reorganization. Moreover, de novo loop formation contributes to differential gene expression, including the dysregulation of genes enriched in mitotic pathways. This leads to the disruptions of cell proliferation in the embryonic brain after genetic ablation of Setdb1 both in vitro and in vivo.

Conclusions
In summary, our study sheds light on the epigenetic regulation of SINEs in mouse neural precursor cells, suggesting their role in maintaining chromatin organization and cell proliferation during neurodevelopment.
Efficient synthesis of limonene production in Yarrowia lipolytica by combinatorial engineering strategies
Authors: Park Young-Kyoung , Sellés Vidal Lara , Bell David , Zabret Jure , Soldat Mladen , Kavšček Martin , Ledesma-Amaro Rodrigo 
Published: July 2024

Abstract
Background
Limonene has a variety of applications in the foods, cosmetics, pharmaceuticals, biomaterials, and biofuels industries. In order to meet the growing demand for sustainable production of limonene at industry scale, it is essential to find an alternative production system to traditional plant extraction. A promising and eco-friendly alternative is the use of microbes as cell factories for the synthesis of limonene.

Results
In this study, the oleaginous yeast Yarrowia lipolytica has been engineered to produce d- and l-limonene. Four target genes, l- or d-LS (limonene synthase), HMG (HMG-CoA reductase), ERG20 (geranyl diphosphate synthase), and NDPS1 (neryl diphosphate) were expressed individually or fused together to find the optimal combination for higher limonene production. The strain expressing HMGR and the fusion protein ERG20-LS was the best limonene producer and, therefore, selected for further improvement. By increasing the expression of target genes and optimizing initial OD, 29.4 mg/L of l-limonene and 24.8 mg/L of d-limonene were obtained. We also studied whether peroxisomal compartmentalization of the synthesis pathway was beneficial for limonene production. The introduction of d-LS and ERG20 within the peroxisome improved limonene titers over cytosolic expression. Then, the entire MVA pathway was targeted to the peroxisome to improve precursor supply, which increased d-limonene production to 47.8 mg/L. Finally, through the optimization of fermentation conditions, d-limonene production titer reached 69.3 mg/L.

Conclusions
In this work, Y. lipolytica was successfully engineered to produce limonene. Our results showed that higher production of limonene was achieved when the synthesis pathway was targeted to the peroxisome, which indicates that this organelle can favor the bioproduction of terpenes in yeasts. This study opens new avenues for the efficient synthesis of valuable monoterpenes in Y. lipolytica.
Phosphate limitation enhances malic acid production on nitrogen-rich molasses with Ustilago trichophora
Authors: Grebe Luca Antonia , Lichtenberg Philipp Georg , Hürter Katharina , Forsten Eva , Miebach Katharina , Büchs Jochen , Magnus Jørgen Barsett 
Published: July 2024

Abstract
Background
An important step in replacing petrochemical products with sustainable, cost-effective alternatives is the use of feedstocks other than, e.g., pure glucose in the fermentative production of platform chemicals. Ustilaginaceae offer the advantages of a wide substrate spectrum and naturally produce a versatile range of value-added compounds under nitrogen limitation. A promising candidate is the dicarboxylic acid malic acid, which may be applied as an acidulant in the food industry, a chelating agent in pharmaceuticals, or in biobased polymer production. However, fermentable residue streams from the food and agricultural industry with high nitrogen content, e.g., sugar beet molasses, are unsuited for processes with Ustilaginaceae, as they result in low product yields due to high biomass and low product formation.

Results
This study uncovers challenges in evaluating complex feedstock applicability for microbial production processes, highlighting the role of secondary substrate limitations, internal storage molecules, and incomplete assimilation of these substrates. A microliter-scale screening method with online monitoring of microbial respiration was developed using malic acid production with Ustilago trichophora on molasses as an application example. Investigation into nitrogen, phosphate, sulphate, and magnesium limitations on a defined minimal medium demonstrated successful malic acid production under nitrogen and phosphate limitation. Furthermore, a reduction of nitrogen and phosphate in the elemental composition of U. trichophora was revealed under the respective secondary substrate limitation. These adaptive changes in combination with the intricate metabolic response hinder mathematical prediction of product formation and make the presented screening methodology for complex feedstocks imperative. In the next step, the screening was transferred to a molasses-based complex medium. It was determined that the organism assimilated only 25% and 50% of the elemental nitrogen and phosphorus present in molasses, respectively. Due to the overall low content of bioavailable phosphorus in molasses, the replacement of the state-of-the-art nitrogen limitation was shown to increase malic acid production by 65%.

Conclusion
The identification of phosphate as a superior secondary substrate limitation for enhanced malic acid production opens up new opportunities for the effective utilization of molasses as a more sustainable and cost-effective substrate than, e.g., pure glucose for biobased platform chemical production.
Amphiphilic block and random copolymers: aggregation and hydrophobic modification on metal-free tanned collagen fibers
Authors: Yi Yudan , Fan Xinxin , Li Qijun , Wang Ya-nan 
Published: July 2024

AbstractHydrophobicity enhancement of metal-free leather, which is crucial for improving its comprehensive performance, can be achieved by using amphiphilic copolymer retanning agents. However, the relationship between the sequential structure and the hydrophobic modification effect of amphiphilic copolymers remains unclear. Herein, an amphiphilic block copolymer was synthesized using stearyl methacrylate and 2-(dimethylamino)ethyl methacrylate via atom transfer radical polymerization, and the corresponding random copolymer with similar monomer compositions and molecular weights was prepared for comparison. The aggregation behavior of block and random copolymers was investigated. DLS and TEM results indicate that the block copolymer exhibits a larger aggregate size than the corresponding random copolymer. Molecular dynamics simulations suggest that the block copolymer aggregate exhibit a thicker hydrophilic shell and more concentrated distribution of cationic DMA block than the random copolymer aggregate. Subsequently, the block and random copolymers were used for the hydrophobic modification of metal-free tanned collagen fibers (CFs). The block copolymer shows superior binding capacity to CFs than the random one because of its larger size and more concentrated charge distribution. Hence, the block copolymer can form a dense and uniform hydrophobic film on the surface of collagen fibrils and endow CFs with higher hydrophobicity than the random one. This work provides theoretical guidance for modulating the hydrophobicity of CFs by tailoring the sequential structure of amphiphilic copolymers, which is expected to inspire the manufacturing of high-performance metal-free leather.
Graphical Abstract
Antioxidant activity and phenolic content of herbal infusions from medicinal plants used in Argentina
Authors: Gallia María Celeste , Ferrari Ana , Bajda Leonardo , Bongiovanni Guillermina Azucena 
Published: July 2024

AbstractCurrently, teas and herbal infusions represent an important part of the human diet. Most contain phenolic compounds with high antioxidant activity, usually associated with human health protective functions. This attribute defines teas and infusions as nutraceutical foods. In Argentina, several native species are traditionally used for medical purposes. Some of those species are Larrea cuneifolia, Larrea nitida, Grindelia chiloensis, Pteromonnina dictyocarpa, Mandevilla laxa, and Monttea aphylla. The objectives of this study were to analyze the antioxidant power and the scavenging capacity of infusions obtained from those six medicinal plants, to characterize the phenolic profile, and to study in vitro their safety or cytotoxicity. Additionally, the potential use of two infusions as antioxidant additives in a food model was evaluated. The results indicated that the analyzed plant species are rich in phenolic acids (e.g., caffeic, ferulic, and chlorogenic acid), and flavonoids (e.g., quercetin and kaempferol), with high antioxidant power. The infusion blend obtained with G. chiloensis and L. cuneifolia exhibited the highest value of antioxidant capacity measured with the FRAP technique (193.4 μg EAA/mg DW). On the other hand, L. cuneifolia infusion showed the greatest antioxidant capacity determined by FRAP (131.9 ± 5.2 μg EAA/mg DW) and DPPH assays (0.453 mL/mg s). Additionally, L. cuneifolia infusion showed the highest phenolic content (232.8 μg GAE/mg DW) and flavonoid content (153.3 μg QE/mg DW). None of the infusions showed toxicity in mammalian cells, except for G. chiloensis. Furthermore, the L. cuneifolia and L. nitida infusions showed a high inhibitory effect on lipid oxidation in ground beef (55% and 51% at 4 days of storage, respectively). The results suggest that the studied infusions are safe and a rich source of antioxidants, which supports their use in traditional medicine. However, further exhaustive studies of G. chiloensis infusion are needed to ensure its safety, as it has shown cytotoxicity. Besides, it is worthwhile to advance the study of L. cuneifolia and L. nitida as sources of dietary antioxidants, due to their high antioxidant power and ability to protect against lipid peroxidation.
Graphical Abstract
Mechanical mitral valve endurance in children under 2 years
Authors: Mashali Mohamed H. , Elmahrouk Ahmed F. , Ahmad Zaheer , Abdulrahman Osama , Galleon Anas Farag , Al-Kouatli Amjad , Jamjoom Ahmed A. , Zahr Riad Abou 
Published: July 2024

Abstract
Background
The management of mitral valve disease in young children is challenging. Mechanical mitral valves could provide long-term durability; however, the need for anticoagulation increases the risk profile of mechanical valves. We report our experience in mechanical mitral valve replacement (MVR) in children under 2 years of age and evaluate factors affecting the outcomes.
The study included all patients younger than 2 years who underwent mechanical MVR between 2000 and 2023. The study outcomes were mitral valve reoperation, bleeding, valve-related thrombosis, and survival.

Results
Twenty-three patients were included, with a mean age of 10.2 ± 5.9 months. The mitral valve sizes ranged from 16 to 25 mm, and 6 (26%) were placed in the supra-annular position. Complete heart block occurred in seven patients (30%), and operative mortality occurred in three patients (13%). Postoperative warfarin was used in 17 patients (74%). After discharge, bleeding occurred in five patients (22%), four were managed conservatively, and one had intracranial hemorrhage treated with craniotomy. Nine patients (39%) had valve-related thrombosis; two underwent reoperation, while seven were treated with alteplase in 26 patients. Valve-related thrombosis was more common in patients with supra-annular valves (p < 0.001) and in those who were not on warfarin (p < 0.001). A total of seven patients (30%) underwent redo MVR, and redo was more common in young patients (p = 0.029) and in patients with supra-annular valves (p < 0.001). Survival of the whole cohort was 73% at 5 years. Among the annular position group, 5-year survival was 88%, while among the supra-annular position group, survival was 50% after 3 months and 25% after 14 months (p = 0.009).

Conclusions
Mechanical MVR in children younger than 2 years is associated with high complication rates, including thrombosis and bleeding. The supra-annular valve position appears to be a risk factor for thrombosis and reoperation. Anticoagulation with warfarin remains challenging. However, further studies evaluating alternative options are needed.

Graphical Abstract
Design of Y-shaped tri-band rectangular slot DGS patch antenna at sub-6 GHz frequency range for 5G communication
Authors: Singh Ajay , Joshi Sunil 
Published: July 2024

AbstractThis paper presents the design and development of a rectangular slot DGS patch antenna fed by a microstrip line, designed to operate across three distinct frequency bands at 4.0 GHz, 4.9 GHz, and 5.5 GHz for 5G wireless communication applications. The antenna design outlined in this study is implemented on a Fr-4 substrate with dimensions measuring 50.5 × 41.12 × 1.5 mm3. The antenna gains at three frequency bands are 2.69 dBi, 7.27 dBi, and 11.37 dBi having impedance bandwidths of 9%, 8.9%, and 5.1%, respectively. The attained bandwidths are 356 MHz, 443 MHz, and 287 MHz for the respective frequency bands. The radiation efficiencies of the proposed antenna are 90%, 82%, and 79% of the three respective frequencies. Antenna 1 in this study exhibits single-band behavior, effectively covering the single frequency band which is 5.5 GHz (5.3578–5.9519 GHz) 5G unlicensed band 5-GHz WLAN IEEE 802.11a frequency. On the other hand, Antenna 2 demonstrates dual-band characteristics spanning the S-band 3.7 GHz (3.5619–3.8544 GHz) and C-band range 5.1 GHz (4.8496–5.2008 GHz) suitable for mid-band 5G applications. Antenna 3 proposed antenna exhibits a tri-band functionality within the C-band spectrum. The results highlight multiple-band operation, consistent high gain, high directivity, and favorable directional radiation patterns.
Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab (NIVO + RELA + IPI) in advanced melanoma: Results from RELATIVITY-048.
Authors: Ascierto Paolo Antonio , Dummer Reinhard , Gaudy-Marqueste Caroline , Bowyer Samantha , Lipson Evan J. , Ghisoni Eleonora , Middleton Mark R. , Ratto Barbara , Jackson William Joseph , Cheong Alicia , Mukherjee Sourav , Wu Jenny , Long Georgina V. 
Published: July 2024

9504 Background: NIVO (anti–PD-1 antibody) is approved as monotherapy and in combination with either RELA (anti–LAG-3 antibody) or IPI (anti–CTLA-4 antibody) for the treatment of patients (pts) with advanced melanoma. RELATIVITY-048 (NCT03459222) is a phase 1/2, nonrandomized trial evaluating immuno-oncology (I-O) triplets, including NIVO + RELA + IPI, for pts with select solid tumors. This analysis from RELATIVITY-048 focused on NIVO + RELA + IPI use in the advanced melanoma cohort and is the first disclosure from the study. Methods: Pts with advanced melanoma were treated with first-line NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W until progression or unacceptable toxicity. Prior neoadjuvant/adjuvant therapy, including I-O agents, was permitted if completed > 6 mo before enrollment. Pts with controlled brain metastases were allowed to enroll. Primary endpoints were safety and confirmed objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR) per investigator. The secondary endpoint was progression-free survival (PFS) per investigator (median and 6-mo/12-mo rates). Exploratory endpoints included overall survival (OS; median and 12-mo/24-mo rates). Results: In total, 46 pts were treated. Median follow-up was 49.4 mo (range, 0.4–55.0; database lock, Nov. 1, 2023). Median age was 61.0 y, 8.7% had cutaneous acral melanoma, 50.0% were BRAF positive, 73.9% were LAG-3 positive (≥ 1%), 26.1% were tumor cell PD-L1 positive (≥ 1%), and 6.5% had received prior adjuvant therapy. Median duration of treatment was 5.0 mo (range, 0.0–49.0). NIVO + RELA + IPI had a confirmed ORR of 58.7% and a 48-mo OS rate of 71.7% (table). Any-grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%) and 18 pts (39.1%), respectively. Any-grade TRAEs led to treatment discontinuation in 19 pts (41.3%). Deaths due to TRAEs occurred in 2 pts (4.3%; rectal hemorrhage and dyspnea [n = 1], immune-mediated myositis [n = 1]). Conclusions: In RELATIVITY-048, NIVO + RELA + IPI demonstrated encouraging efficacy, with a confirmed ORR of 58.7% and a 48-mo OS rate of 69.1%. There were no new safety signals with NIVO + RELA + IPI, and the safety profile was generally consistent with I-O combinations. Given the small sample size, additional studies are needed to confirm the efficacy and safety of NIVO + RELA + IPI. Clinical trial information: NCT03459222 . [Table: see text]
Development of a novel granulocyte scoring system for use as a predictive/prognostic biomarker in patients with advanced melanoma undergoing treatment with combination immunotherapy.
Authors: Julve Max , Wong Yien Ning Sophia , Diez de los Rios Riobo Margarita , Garitaonaindia Yago , Rosero Diana I. , Needham Jazmine , Soto Juan Jose , Beland Chloe , Le Ha Mo Linh , Larkin James , Furness Andrew J.S. 
Published: July 2024

9551 Background: Despite the implementation of immune checkpoint inhibition (ICI) for patients with metastatic melanoma, there remains an unmet clinical need for predictive/prognostic biomarkers to determine, from outset, which patients will derive benefit. Recent literature has suggested a significant role for granulocyte subsets in the development of resistance to systemic therapies, with an associated role in adaptive immunity. Methods: We sought to establish a novel immunological scoring system to use as a predictive/prognostic biomarker in patients with advanced melanoma being treated with ICI. In this retrospective, single centre study evaluating patients with advanced melanoma treated with combination ipilimumab and nivolumab, progression free survival (PFS) and overall survival (OS) were compared between groups defined by neutrophil, lymphocyte, eosinophil, monocyte and basophil counts. Data from 226 patients was collected at baseline, week 3, week 6, first response scan and at progression. Baseline and week 3 data was the focus of this primary analysis. Kaplan-Meier estimation and Cox regression analysis were performed. Results: Univariate analysis demonstrated that absolute neutrophil, eosinophil and basophil count strongly associates with PFS and OS outcomes at week 3. Combination of these counts into a novel neutrophil to eosinophil + basophil ratio (NEBR, (N/(E+B)) was assessed as a scoring system. High NEBR was associated with poorer PFS and OS at baseline and week 3 with consistently superior predictive/prognostic value than the well-established neutrophil to lymphocyte ratio (NLR). After accounting for covariates including concurrent steroids, infection and LDH, high NEBR remained significantly associated with worse PFS at baseline and poorer PFS and OS at week 3. Conclusions: Our findings highlight NEBR as a novel immunotherapeutic predictive/prognostic biomarker with potential clinical utility that warrants further investigation in patients with advanced melanoma and across other tumour groups. Further validation will be required through independent external datasets. [Table: see text]
Ultra-hypofractionated adjuvant radiation therapy for breast cancer (UK FAST-Forward trial): A real life scenario analysis in a developing country.
Authors: Aguiar Rennê Bart , Ferrari Ramon , Franco Leonardo Oliveira , Almeida Carlos Veloso , Canary Paulo , Przybysz Daniel 
Published: July 2024

e12501 Background: Selected patients showed non-inferior outcomes after conservative surgery for early breast cancer in the FAST-Forward UK (26Gy in 5 fractions) when compared to standard to date treatment. This study triggered an important change in radiation therapy routines across the world. We aimed to establish a pattern of treatment related events at a third-world country cancer center. Methods: We retrospectively analyzed all patients treated with 26Gy in 5 fractions (1 week) from January 2020 to June 2023. All data was exported and analyzed for demographics. A clinical profile was traced, dosimetric parameters and side effects assessed based on individual inquiries to each patient, per and post treatment. A strict medical record was kept in order to understand patterns of side effects and results. Results: 101 individuals were identified. Mean age was 64 years, 48 (47%) patients experienced radiation dermatitis of any grade, 33 (32%) grade 1, 9 (8%) grade 2, 6 grade 3 or 4 (5%). Patients older than 60 years showed to be a significant factor for dermatitis development (34 over a total of 48 - 70%) and 8 (53%) over 15 had grade 2 or higher dermatitis. 27 (26%) developed radiation dermatitis during sessions. 21 (20%) took 7 or less days to heal; 27 (26%) had a recovery longer than one week at an average age of 65 years - being the majority of dermatitis grade 1. Reported toxicities were sharp pain 31 (30%), burning pain 24 (23%), edema 17 (16%) and pruritus 5 (4%). At the time of this study was completed, 3 reported deaths (2%) were reported - with a 97% rate of survival. Conclusions: The FAST-Forward trial regimen has 3 years since its publication. Our study shows that in a selected group of breast cancer patients, this novel model has shown to be a safe alternative for adjuvant radiation therapy following breast conservative surgery, results corroborating with published data. To the best of our knowledge, this is the largest single center group analyzed and published.