bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic analysis of human RNA binding motif protein 48 (RBM48) reveals an essential role in U12-type intron splicing
Authors: Siebert Amy E , Corll Jacob , Paige Gronevelt J , Levine Laurel , Hobbs Linzi M , Kenney Catalina , Powell Christopher L E , Battistuzzi Fabia U , Davenport Ruth , Mark Settles A , Brad Barbazuk W , Westrick Randal J , Madlambayan Gerard J , Lal Shailesh 
Published: August 2022

Abstract
U12-type or minor introns are found in most multicellular eukaryotes and constitute ∼0.5% of all introns in species with a minor spliceosome. Although the biological significance for the evolutionary conservation of U12-type introns is debated, mutations disrupting U12 splicing cause developmental defects in both plants and animals. In human hematopoietic stem cells, U12 splicing defects disrupt proper differentiation of myeloid lineages and are associated with myelodysplastic syndrome, predisposing individuals to acute myeloid leukemia. Mutants in the maize ortholog of RNA binding motif protein 48 (RBM48) have aberrant U12-type intron splicing. Human RBM48 was recently purified biochemically as part of the minor spliceosome and shown to recognize the 5′ end of the U6atac snRNA. In this report, we use CRISPR/Cas9-mediated ablation of RBM48 in human K-562 cells to show the genetic function of RBM48. RNA-seq analysis comparing wild-type and mutant K-562 genotypes found that 48% of minor intron-containing genes have significant U12-type intron retention in RBM48 mutants. Comparing these results to maize rbm48 mutants defined a subset of minor intron-containing genes disrupted in both species. Mutations in the majority of these orthologous minor intron-containing genes have been reported to cause developmental defects in both plants and animals. Our results provide genetic evidence that the primary defect of human RBM48 mutants is aberrant U12-type intron splicing, while a comparison of human and maize RNA-seq data identifies candidate genes likely to mediate mutant phenotypes of U12-type splicing defects.
Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate
Authors: Kolterud Åsa , Välimäki Niko , Kuisma Heli , Patomo Joonatan , Ilves Sini T , Mäkinen Netta , Kaukomaa Jaana , Palin Kimmo , Kaasinen Eevi , Karhu Auli , Pasanen Annukka , Bützow Ralf , Heikinheimo Oskari , Kopp Kallner Helena , Aaltonen Lauri A 
Published: August 2022

AbstractPrecision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37–13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.
miR164g-MsNAC022 acts as a novel module mediating drought response by transcriptional regulation of reactive oxygen species scavenging systems in apple
Authors: Peng Xiang , Feng Chen , Wang Yan-Tao , Zhang Xiang , Wang Yan-Yan , Sun Yue-Ting , Xiao Yu-Qin , Zhai Ze-Feng , Zhou Xin , Du Bing-Yang , Wang Chao , Liu Yang , Li Tian-Hong 
Published: August 2022

Abstract
Under drought stress, reactive oxygen species (ROS) overaccumulate as a secondary stress that impairs plant performance and thus severely reduces crop yields. The mitigation of ROS levels under drought stress is therefore crucial for drought tolerance. MicroRNAs (miRNAs) are critical regulators of plant development and stress responses. However, the complex molecular regulatory mechanism by which they function during drought stress, especially in drought-triggered ROS scavenging, is not fully understood. Here, we report a newly identified drought-responsive miRNA, miR164g, in the wild apple species Malus sieversii and elucidate its role in apple drought tolerance. Our results showed that expression of miR164g is significantly inhibited under drought stress and it can specifically cleave transcripts of the transcription factor MsNAC022 in M. sieversii. The heterologous accumulation of miR164g in Arabidopsis thaliana results in enhanced sensitivity to drought stress, while overexpression of MsNAC022 in Arabidopsis and the cultivated apple line ‘GL-3’ (Malus domestica Borkh.) lead to enhanced tolerance to drought stress by raising the ROS scavenging enzymes activity and related genes expression levels, particularly PEROXIDASE (MsPOD). Furthermore, we showed that expression of MsPOD is activated by MsNAC022 in transient assays. Interestingly, Part1 (P1) region is the key region for the positive regulation of MsPOD promoter by MsNAC022, and the different POD expression patterns in M. sieversii and M. domestica is attributed to the specific fragments inserted in P1 region of M. sieversii. Our findings reveal the function of the miR164g-MsNAC022 module in mediating the drought response of M. sieversii and lay a foundation for breeding drought-tolerant apple cultivars.
Quantitative Fecal Microbiota Profiles Relate to Therapy Response During Induction With Tumor Necrosis Factor α Antagonist Infliximab in Pediatric Inflammatory Bowel Disease
Authors: Höyhtyä Miikka , Korpela Katri , Saqib Schahzad , Junkkari Sofia , Nissilä Eija , Nikkonen Anne , Dikareva Evgenia , Salonen Anne , de Vos Willem M , Kolho Kaija-Leena 
Published: August 2022

Abstract

Background
The role of intestinal microbiota in inflammatory bowel diseases is intensively researched. Pediatric studies on the relation between microbiota and treatment response are sparse. We aimed to determine whether absolute abundances of gut microbes characterize the response to infliximab induction in pediatric inflammatory bowel disease.

Methods
We recruited pediatric patients with inflammatory bowel disease introduced to infliximab at Children’s Hospital, University of Helsinki. Stool samples were collected at 0, 2, and 6 weeks for microbiota and calprotectin analyses. We defined treatment response as fecal calprotectin value &lt;100 µg/g at week 6. Intestinal microbiota were analyzed by 16S ribosomal RNA gene amplicon sequencing using the Illumina MiSeq platform. We analyzed total bacterial counts using quantitative polymerase chain reaction and transformed the relative abundances into absolute abundances based on the total counts.

Results
At baseline, the intestinal microbiota in the treatment responsive group (n = 10) showed a higher absolute abundance of Bifidobacteriales and a lower absolute abundance of Actinomycetales than nonresponders (n = 19). The level of inflammation according to fecal calprotectin showed no statistically significant association with the absolute abundances of fecal microbiota. The results on relative abundances differed from the absolute abundances. At the genus level, the responders had an increased relative abundance of Anaerosporobacter but a reduced relative abundance of Parasutterella at baseline.

Conclusions
High absolute abundance of Bifidobacteriales in the gut microbiota of pediatric patients reflects anti-inflammatory characteristics associated with rapid response to therapy. This warrants further studies on whether modification of pretreatment microbiota might improve the outcomes.
Use of IBD Drugs in Patients With Hepatobiliary Comorbidities: Tips and Tricks
Authors: Massironi Sara , Pirola Lorena , Mulinacci Giacomo , Ciaccio Antonio , Viganò Chiara , Palermo Andrea , Zilli Alessandra , Invernizzi Pietro , Danese Silvio 
Published: August 2022

Abstract
Advanced therapies (biologic agents and small molecules) for inflammatory bowel diseases (IBD) have radically changed the management of these diseases during the last decade. Data about these drugs in patients with hepatic disorders derive mainly from real-life studies, as these conditions often represent an exclusion criterion from pivotal drug developmental trials. However, IBD patients sometimes have concomitant liver diseases. Nonalcoholic fatty liver disease is the most prevalent hepatic comorbidity, whereas viral hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, and hepatic vascular disorders are less frequent. This review aimed at describing the real-life data about the use of advanced therapies for IBD in patients with concomitant hepatobiliary disorders. Hepatitis B virus and hepatitis C virus infections do not represent an absolute contraindication for novel IBD therapeutic agents. Data from the literature suggest a safe hepatobiliary profile of biologic agents and small molecules in the case of nonalcoholic fatty liver disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and portal vein thrombosis. Consequently, although the liver disease does not affect a different therapeutic approach in patients with concomitant IBD and liver disease, a close risk/benefit analysis for each drug should be performed in these patients, especially in cirrhotic patients and in the postliver transplant setting.
Comparison of pharmacokinetics and stability of generics of cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs: an intravenous bioequivalence study in healthy volunteers
Authors: Bergmann Felix , Wulkersdorfer Beatrix , Oesterreicher Zoe , Bauer Martin , al Jalali Valentin , Nussbaumer-Pröll Alina , Wölfl-Duchek Michael , Jorda Anselm , Lackner Edith , Reiter Birgit , Stimpfl Thomas , Ballarini Nicolas , König Franz , Zeitlinger Markus 
Published: August 2022

Abstract

Objectives
The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs.

Methods
In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS.

Results
Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4–99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1–103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1–119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4–101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9–104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4–99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7–105.8)]. Accordingly, similar ratios of AUC0–t were observed for Cefepime-MIP/Maxipime [91.1 (87.6–94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5–103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3–106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3–96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0–102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4–96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3–103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions.

Conclusions
Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators.
Comprehension, utility, and preferences of prostate cancer survivors for visual timelines of patient-reported outcomes co-designed for limited graph literacy: meters and emojis over comics
Authors: Snyder Lauren E , Phan Daniel F , Williams Kristen C , Piqueiras Eduardo , Connor Sarah E , George Sheba , Kwan Lorna , Villatoro Chavez Jefersson , Tandel Megha D , Frencher Stanley K , Litwin Mark S , Gore John L , Hartzler Andrea L 
Published: August 2022

Abstract

Objective
Visual timelines of patient-reported outcomes (PRO) can help prostate cancer survivors manage longitudinal data, compare with population averages, and consider future trajectories. PRO visualizations are most effective when designed with deliberate consideration of users. Yet, graph literacy is often overlooked as a design constraint, particularly when users with limited graph literacy are not engaged in their development. We conducted user testing to assess comprehension, utility, and preference of longitudinal PRO visualizations designed for prostate cancer survivors with limited literacy.

Materials and methods
Building upon our prior work co-designing longitudinal PRO visualizations with survivors, we engaged 18 prostate cancer survivors in a user study to assess 4 prototypes: Meter, Words, Comic, and Emoji. During remote sessions, we collected data on prototype comprehension (gist and verbatim), utility, and preference.

Results
Participants were aged 61–77 (M = 69), of whom half were African American. The majority of participants had less than a college degree (95%), had inadequate health literacy (78%), and low graph literacy (89%). Among the 4 prototypes, Meter had the best gist comprehension and was preferred. Emoji was also preferred, had the highest verbatim comprehension, and highest rated utility, including helpfulness, confidence, and satisfaction. Meter and Words both rated mid-range for utility, and Words scored lower than Emoji and Meter for comprehension. Comic had the poorest comprehension, lowest utility, and was least preferred.

Discussion
Findings identify design considerations for PRO visualizations, contributing to the knowledge base for visualization best practices. We describe our process to meaningfully engage patients from diverse and hard-to-reach groups for remote user testing, an important endeavor for health equity in biomedical informatics.

Conclusion
Graph literacy is an important design consideration for PRO visualizations. Biomedical informatics researchers should be intentional in understanding user needs by involving diverse and representative individuals during development.
Genus Lupinus (Fabaceae): a review of ethnobotanical, phytochemical and biological studies
Authors: Ishaq Ali Raza , El-Nashar Heba A S , Younis Tahira , Mangat Muhammad Asad , Shahzadi Mashal , Ul Haq Amina Shamsheer , El-Shazly Mohamed 
Published: August 2022

Abstract

Objectives
Lupinus is a large and diverse genus comprising approximately 200 species, belonging to the family Fabaceae. Lupinus plants have been used for heart stimulants, nerves, urinary tract infections, skin disorders, and psoriasis in folk medicine. This review aims to recap the traditional medicinal uses, nutritional value, phytochemical profile, and biological activities of Lupinus species.

Key findings
From the literature survey, Lupinus is considered as a factory of various phytochemicals like flavonoids, iso-flavonoids, alkaloids, triterpenoids. The presence of proteins, essential fatty acids, and amino acids, as well as alkaloids, minerals, and dietary fibers, indicated that the plants in this genus had a high nutritional value. The Lupinus extracts displayed promising antidiabetic, anticancer, antimicrobial, antidiabetic, antihypertensive, antioxidant, anti-inflammatory, and antimicrobial activities.

Conclusions
The current review provides updated information that could drive the researchers for further studies. The in vitro and in vivo experiments have demonstrated various pharmacological properties. Some pharmacokinetic and toxicological investigations are warranted to ensure its safety and validity for human use.
Chemically targeting the redox switch in AP1 transcription factor ΔFOSB
Authors: Kumar Ashwani , Aglyamova Galina , Yim Yun Young , Bailey Aaron O , Lynch Haley M , Powell Reid T , Nguyen Nghi D , Rosenthal Zachary , Zhao Wen-Ning , Li Yi , Chen Jianping , Fan Shanghua , Lee Hubert , Russell William K , Stephan Clifford , Robison Alfred J , Haggarty Stephen J , Nestler Eric J , Zhou Jia , Machius Mischa , Rudenko Gabby 
Published: August 2022

Abstract
The AP1 transcription factor ΔFOSB, a splice variant of FOSB, accumulates in the brain in response to chronic insults such as exposure to drugs of abuse, depression, Alzheimer's disease and tardive dyskinesias, and mediates subsequent long-term neuroadaptations. ΔFOSB forms heterodimers with other AP1 transcription factors, e.g. JUND, that bind DNA under control of a putative cysteine-based redox switch. Here, we reveal the structural basis of the redox switch by determining a key missing crystal structure in a trio, the ΔFOSB/JUND bZIP domains in the reduced, DNA-free form. Screening a cysteine-focused library containing 3200 thiol-reactive compounds, we identify specific compounds that target the redox switch, validate their activity biochemically and in cell-based assays, and show that they are well tolerated in different cell lines despite their general potential to bind to cysteines covalently. A crystal structure of the ΔFOSB/JUND bZIP domains in complex with a redox-switch-targeting compound reveals a deep compound-binding pocket near the DNA-binding site. We demonstrate that ΔFOSB, and potentially other, related AP1 transcription factors, can be targeted specifically and discriminately by exploiting unique structural features such as the redox switch and the binding partner to modulate biological function despite these proteins previously being thought to be undruggable.
A deafness-associated mitochondrial DNA mutation caused pleiotropic effects on DNA replication and tRNA metabolism
Authors: Meng Feilong , Jia Zidong , Zheng Jing , Ji Yanchun , Wang Jing , Xiao Yun , Fu Yong , Wang Meng , Ling Feng , Guan Min-Xin 
Published: August 2022

Abstract
In this report, we investigated the molecular mechanism underlying a deafness-associated m.5783C &gt; T mutation that affects the canonical C50-G63 base-pairing of TΨC stem of tRNACys and immediately adjacent to 5′ end of light-strand origin of mitochondrial DNA (mtDNA) replication (OriL). Two dimensional agarose gel electrophoresis revealed marked decreases in the replication intermediates including ascending arm of Y-fork arcs spanning OriL in the mutant cybrids bearing m.5783C &gt; T mutation. mtDNA replication alterations were further evidenced by decreased levels of PolγA, Twinkle and SSBP1, newly synthesized mtDNA and mtDNA contents in the mutant cybrids. The m.5783C &gt; T mutation altered tRNACys structure and function, including decreased melting temperature, conformational changes, instability and deficient aminoacylation of mutated tRNACys. The m.5783C &gt; T mutation impaired the 5′ end processing efficiency of tRNACys precursors and reduced the levels of tRNACys and downstream tRNATyr. The aberrant tRNA metabolism impaired mitochondrial translation, which was especially pronounced effects in the polypeptides harboring higher numbers of cysteine and tyrosine codons. These alterations led to deficient oxidative phosphorylation including instability and reduced activities of the respiratory chain enzyme complexes I, III, IV and intact supercomplexes overall. Our findings highlight the impact of mitochondrial dysfunction on deafness arising from defects in mitochondrial DNA replication and tRNA metabolism.
Exploration and analysis of R-loop mapping data with RLBase
Authors: Miller Henry E , Montemayor Daniel , Li Janet , Levy Simon A , Pawar Roshan , Hartono Stella , Sharma Kumar , Frost Bess , Chedin Frédéric , Bishop Alexander J R 
Published: August 2022

Abstract
R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. In 2012, Ginno et al. introduced the first R-loop mapping method. Since that time, dozens of R-loop mapping studies have been conducted, yielding hundreds of publicly available datasets. Current R-loop databases provide only limited access to these data. Moreover, no web tools for analyzing user-supplied R-loop datasets have yet been described. In our recent work, we reprocessed 810 R-loop mapping samples, building the largest R-loop data resource to date. We also defined R-loop consensus regions and developed a framework for R-loop data analysis. Now, we introduce RLBase, a user-friendly database that provides the capability to (i) explore hundreds of public R-loop mapping datasets, (ii) explore R-loop consensus regions, (iii) analyze user-supplied data and (iv) download standardized and reprocessed datasets. RLBase is directly accessible via the following URL: https://gccri.bishop-lab.uthscsa.edu/shiny/rlbase/.
In vivofunctional characterization of EGFR variants identifies novel drivers of glioblastoma
Authors: Yu Kwanha , Kong Kathleen , Lozzi Brittney , Luna-Figueroa Estefania , Cervantes Alexis , Curry Rachel , Mohila Carrie A , Rao Ganesh , Jalali Ali , Mills Gordon B , Scott Kenneth L , Deneen Benjamin 
Published: August 2022

AbstractBackgroundGlioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering “driver” and “passenger” events amongst the vast volume of information.MethodsWe utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen.ResultsOur screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through which A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models.ConclusionsEGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drives glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.
Population sorting and human capital accumulation
Authors: Azarnert Leonid V 
Published: August 2022

Abstract
This article analyses the effect of population sorting on economic growth. The analysis is performed in a two-region growth model with endogenous fertility, in which public knowledge spillovers from the more advanced core amplify the productivity of investment in children’s human capital in the periphery. I show how migration affects the inter-temporal evolution of human capital in each of the regions and the economy as a whole. I discuss how public policy interventions can help increase the per-capita human capital levels, if free uncontrolled migration leads to a reduction in human capital accumulation. I also analyse how migration and public policy interventions may affect population growth.