bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Roles for SETα and SETβ in Early Cell Fate Decisions
Authors: Lim Patrick Siang Lin , Meshorer Eran 
Published: September 2024

AbstractSET, the nuclear proto-oncogene, is primarily expressed as SETα in embryonic stem cells. Upon pluripotency exit, a transcriptional switch driven by alternative promoters causes SETβ to largely replace SETα expression. Functional distinctions between the two isoforms have been difficult to ascertain, partly due to the redundancy between SETα and SETβ in their protein structure and activity. In this study, we use embryonic stem cells (ESCs) with inducible SET isoform-specific expression to investigate the differences between both SET isoforms. Time-course RNA-seq analyses in SET-KO backgrounds as well as isoform-specific ChIP-seq experiments reveal regulatory functions for SETα and SETβ. Despite sharing many binding sites and binding partners, SETα has unique regulatory functions on its target genes, while SETβ downregulates FGF4. As KLF5 specifically regulates SETα, this implicates SET isoform switching at the KLF5/FGF signalling axis during primitive endoderm specification. Together, we propose a model of how distinct roles of SETα and SETβ may regulate cell identity in the early blastocyst.
DivergentPlasmodiumkinases drive MTOC, kinetochore and axoneme organisation in male gametogenesis
Authors: Yanase Ryuji , Zeeshan Mohammad , Ferguson David J. P. , Marcus Robert , Brady Declan , Bottrill Andrew R. , Holder Anthony A. , Guttery David S. , Tewari Rita 
Published: September 2024

AbstractSexual development and male gamete formation of the malaria parasite in the mosquito midgut is governed by rapid endomitosis in the activated male gametocyte. This process is highly regulated by protein phosphorylation, specifically by three divergent male-specific protein kinases (PKs): CDPK4, SRPK1 and MAP2. Here, we localise each PK during rapid male gamete formation using live-cell imaging, identify their putative substrates by immunoprecipitation, and determine the morphological consequences of their absence using ultrastructure expansion and transmission electron microscopy. Each PK has a distinct location in either the nuclear or cytoplasmic compartment. Protein interaction studies revealed that CDPK4 and MAP2 interact with key drivers of rapid DNA replication, while SRPK1 is involved in RNA translation. The absence of each PK results in severe defects in either microtubule organising centre (MTOC) organisation, kinetochore segregation or axoneme formation. This study reveals the crucial role of these PKs during endomitosis in formation of the flagellated male gamete and uncovers some of their potential substrates that drive this process.Summary blurbThis study reveals how Plasmodium kinases regulate MTOC, axoneme and kinetochore organisation in male gametogenesis, providing key insights into potential targets for malaria transmission control.
The expansion and diversification of epigenetic regulatory networks underpins major transitions in the evolution of land plants
Authors: Petroll Romy , Papareddy Ranjith K. , Krela Rafal , Laigle Alice , Riviere Quentin , Bišová Kateřina , Mozgová Iva , Borg Michael 
Published: September 2024

AbstractEpigenetic silencing is essential for regulating gene expression and cellular diversity in eukaryotes. While DNA and H3K9 methylation silence transposable elements (TEs), H3K27me3 marks deposited by the Polycomb repressive complex 2 (PRC2) silence varying proportions of TEs and genes across different lineages. Despite the major development role epigenetic silencing plays in multicellular eukaryotes, little is known about how epigenetic regulatory networks were shaped over evolutionary time. Here, we analyse epigenomes from diverse species across the green lineage to infer the chronological epigenetic recruitment of genes during land plant evolution. We first reveal the nature of plant heterochromatin in the unicellular chlorophyte microalgaChlorella sorokinianaand identify several genes marked with H3K27me3, highlighting the deep origin of PRC2-regulated genes in the green lineage. By incorporating genomic phylostratigraphy, we show how genes of differing evolutionary age occupy distinct epigenetic states in plants. While young genes tend to be silenced by H3K9 methylation, genes that emerged in land plants are preferentially marked with H3K27me3, some of which form part of a common network of PRC2-repressed genes across distantly-related species. Finally, we analyse the potential recruitment of PRC2 to plant H3K27me3 domains and identify conserved DNA-binding sites of ancient transcription factor (TF) families known to interact with PRC2. Our findings shed light on the conservation and potential origin of epigenetic regulatory networks in the green lineage, while also providing insight into the evolutionary dynamics and molecular triggers that underlie the adaptation and elaboration of epigenetic regulation, laying the groundwork for its future consideration in other eukaryotic lineages.
Lupus flare and recurrent lupus nephritis following kidney transplantation in patients with lupus nephritis
Authors: Kim Young‐Eun , Kim Jin‐Myung , Ahn Soo Min , Oh Ji Seon , Kim Yong‐Gil , Lee Chang‐Keun , Yoo Bin , Shin Sung , Hong Seokchan 
Published: September 2024

AbstractBackgroundClinical manifestations and risk factors associated with systemic lupus erythematosus (SLE) flares, including recurrent lupus nephritis (LN), in patients with LN who undergo kidney transplantation have been unclear.MethodsKidney transplant recipients with LN from January 1995 to December 2021 were included in this study. A disease flare was defined as either an increase in the non‐renal SLE disease activity index score or the presence of biopsy‐proven recurrent LN.ResultsAmong a total of 93 patients with LN who underwent kidney transplantation, 11 patients (11.8%) experienced SLE flares during a median follow‐up period of 76.9 months (IQR, 43.0–122.4). The most common clinical manifestations of SLE flares were recurrent LN (4/11, 36.4%) and hematologic manifestations (4/11, 36.4%). Patients who had flares had significantly higher anti‐double‐stranded DNA (anti‐dsDNA) antibody titers both before and after transplantation. Furthermore, an increased anti‐dsDNA antibody level before transplantation was associated with a high risk of an SLE flare (HR, 1.030; p = .008). Conversely, preemptive transplantation was associated with a lower risk of a flare (HR, 0.617; p = .026). The rate of patient death‐censored graft survival was found to be considerably lower in patients with recurrent LN than in those without LN.ConclusionsApproximately 10% of patients with LN experienced an SLE flare after transplantation, with recurrent LN being the most frequent manifestation. Anti‐dsDNA antibody titers before transplantation were significantly related to the risk of an SLE flare. Notably, preemptive transplantation was associated with a reduced risk of flares following transplantation.
Alcohol Feedback, Reflection, and Morning Evaluation (A‐FRAME): Refining and testing feasibility and acceptability of a smartphone‐delivered alcohol intervention for heavy‐drinking young adults
Authors: Merrill Jennifer E. , Gebru Nioud Mulugeta , Peterson Roselyn , López Gabriela , Lau‐Barraco Cathy , Barnett Nancy P. , Carey Kate B. 
Published: September 2024

AbstractBackgroundYoung adults drink heavily and experience negative alcohol consequences. To capitalize on mornings after drinking as an optimal time to intervene, we developed a novel, theory‐based personalized feedback intervention (PFI) called Alcohol Feedback, Reflection, and Morning Evaluation (A‐FRAME), to reduce heavy drinking. An initial prototype was refined via feedback from college students who drink heavily. The goal of the present study was to conduct an open trial to establish feasibility and acceptability of the refined PFI.MethodsThe refined PFI was delivered for 4 weeks to 18 heavy‐drinking young adults (Mage = 22.61, 44% women, 66.7% White, 27.8% Black, 16.7% Asian, 5.6% Native American/Alaskan Indian, 22.2% Hispanic/Latino). Participants completed a goal‐setting procedure, followed by 28 daily surveys. Surveys indicating prior‐day drinking were followed by the option to view personalized feedback (e.g., goal attainment, blood alcohol concentration [BAC], peer norms, protective behaviors). Aggregated feedback was also delivered at the 14‐ and 28‐day marks. Participants completed a post‐test acceptability survey and individual interviews to inform further refinement.ResultsThe response rate to daily surveys was 93.8% and all participants completed study procedures, demonstrating feasibility. Daily feedback was reviewed about half (45.5%) of the time it was offered (i.e., following drinking days). Biweekly feedback was viewed 50% and 56% of the time at 14‐ and 28‐day marks, respectively. Other benchmarks for acceptability were supported by survey and interview results.ConclusionsOpen trial results support the feasibility and acceptability of this theory‐based intervention for heavy‐drinking young adults. A planned randomized controlled trial will evaluate efficacy.
Cholesterol synthesis is essential for the growth of liver metastasis‐prone colorectal cancer cells
Authors: Taniguchi Kumiko , Sugihara Kei , Miura Takashi , Hoshi Daisuke , Kohno Susumu , Takahashi Chiaki , Hirata Eishu , Kiyokawa Etsuko 
Published: September 2024

AbstractMetastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl‐CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol‐dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.
KA‐mediated excitotoxicity induces neuronal ferroptosis through activation of ferritinophagy
Authors: Jiang Yi‐Yue , Wu Wei‐Long , Huang Jia‐Ni , Liu Na , Wang Jing , Wan Xiao‐Rui , Qin Zheng‐Hong , Wang Yan 
Published: September 2024

AbstractObjectivesThis study aims to elucidate the role of Fe2+ overload in kainic acid (KA)‐induced excitotoxicity, investigate the involvement of ferritinophagy selective cargo receptor NCOA4 in the pathogenesis of excitotoxicity.MethodsWestern blotting was used to detect the expression of FTH1, NCOA4, Lamp2, TfR, FPN, and DMT1 after KA stereotaxic injection into the unilateral striatum of mice. Colocalization of Fe2+ with lysosomes in KA‐treated primary cortical neurons was observed by using confocal microscopy. Desferrioxamine (DFO) was added to chelate free iron, a CCK8 kit was used to measure cell viability, and the Fe2+ levels were detected by FerroOrange. BODIPY C11 was used to determine intracellular lipid reactive oxygen species (ROS) levels, and the mRNA levels of PTGS2, a biomarker of ferroptosis, were measured by fluorescent quantitative PCR. 3‐Methyladenine (3‐MA) was employed to inhibit KA‐induced activation of autophagy, and changes in ferritinophagy‐related protein expression and the indicated biomarkers of ferroptosis were detected. Endogenous NCOA4 was knocked down by lentivirus transfection, and cell viability and intracellular Fe2+ levels were observed after KA treatment.ResultsWestern blot results showed that the expression of NCOA4, DMT1, and Lamp2 was significantly upregulated, while FTH1 was downregulated, but there were no significant changes in TfR and FPN. The fluorescence results indicated that KA enhanced the colocalization of free Fe2+ with lysosomes in neurons. DFO intervention could effectively rescue cell damage, reduce intracellular lipid peroxidation, and decrease the increased transcript levels of PTGS2 caused by KA. Pretreatment with 3‐MA effectively reversed KA‐induced ferritinophagy and ferroptosis. Endogenous interference with NCOA4 significantly improved cell viability and reduced intracellular free Fe2+ levels in KA‐treated cells.ConclusionKA‐induced excitotoxicity activates ferritinophagy, and targeting ferritinophagy effectively inhibits downstream ferroptosis. Interference with NCOA4 effectively attenuates KA‐induced neuronal damage. This study provides a potential therapeutic target for excitotoxicity related disease conditions.
IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease
Authors: Rane Shraddha S. , Shellard Elan , Adamson Antony , Eyre Steve , Warren Richard B. 
Published: September 2024

AbstractPsoriasis is an incurable immune‐mediated skin disease, affecting around 1%–3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA‐B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.
Optimization of Minocycline‐Containing Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Real‐World Evidence Study
Authors: Huang Yu , Qiu Shuhan , Guo Yixian , Chen Jinnan , Li Meixuan , Ding Zhaohui , Zhang Wei , Liang Xiao , Lu Hong 
Published: September 2024

ABSTRACTBackgroundThe optimal dosage of minocycline remains unclear for Helicobacter pylori (H. pylori) eradication. We aimed to evaluate the efficacy and safety of four different regimens with minocycline and metronidazole compared to classical bismuth quadruple therapy for H. pylori rescue treatment.Materials and MethodsFrom March 2021 to March 2024, refractory H. pylori‐infected patients with at least two previous treatment failures who received 14‐day therapy with b.i.d. proton pump inhibitor 20 mg and bismuth 220 mg, plus tetracycline 400 mg q.i.d and metronidazole 400 mg q.i.d (BQT), or minocycline 50 mg q.i.d and metronidazole 400 mg q.i.d (PBMn4M4), or minocycline 50 mg t.i.d and metronidazole 400 mg t.i.d (PBMn3M3), or minocycline 50 mg b.i.d and metronidazole 400 mg q.i.d (PBMn2M4), or minocycline 50 mg b.i.d and metronidazole 400 mg t.i.d (PBMn2M3) were included in this retrospective study. H. pylori eradication was assessed by 13C‐urea breath test at least 6 weeks after treatment. All adverse effects during treatment were recorded.ResultsTotally, 823 patients were enrolled: 251 with BQT, 97 with PBMn4M4, 191 with PBMn3M3, 108 with PBMn2M4, and 176 with PBMn2M3. The eradication rates of BQT, PBMn4M4, PBMn3M3, PBMn2M4, and PBMn2M3 were 89.2%, 87.6%, 91.6%, 88.0%, and 91.5%, respectively, by intention‐to‐treat analysis; 96.1%, 97.7%, 97.8%, 96.9%, and 97.6%, respectively, by modified intention‐to‐treat analysis; 97.1%, 97.5%, 97.7%, 96.8%, and 97.6%, respectively, by per‐protocol analysis. Metronidazole resistance did not affect the efficacy of all groups. PBMn2M3 group achieved the greatest compliance and the fewest moderate and severe adverse events.ConclusionsThe novel bismuth‐containing quadruple therapy with a low dose of minocycline and metronidazole is an alternative to classical bismuth quadruple therapy for H. pylori rescue treatment with superior safety and compliance.Trial RegistrationClinicalTrials.gov identifier: NCT06332599
Differentiating clinical characteristics of perianal inflammatory bowel disease from perianal hidradenitis suppurativa
Authors: Yamanaka‐Takaichi Mika , Nadalian Soheila , Loftus Edward V. , Ehman Eric C. , Todd Austin , Grimaldo Anna B. , Yalon Mariana , Matchett Caroline L. , Patel Nisha B. , Isaq Nasro A. , Raffals Laura E. , Wetter David A. , Murphree Dennis H. , Cima Robert R. , Dozois Eric J. , Goldfarb Noah , Tizhoosh Hamid R. , Alavi Afsaneh 
Published: September 2024

AbstractBackgroundPerianal draining tunnels in hidradenitis suppurativa (HS) and perianal fistulizing inflammatory bowel disease (IBD) present diagnostic and management dilemmas.MethodsWe conducted a retrospective chart review of patients with perianal disease evaluated at Mayo Clinic from January 1, 1998, through July 31, 2021. Patients' demographic and clinical data were extracted, and 28 clinical features were collected. After experimenting with several machine learning techniques, random forests were used to select the 15 most important clinical features to construct the diagnostic prediction model to distinguish perianal HS from fistulizing perianal IBD.ResultsA total of 263 patients were included (98 with HS, 100 with IBD, and 65 with both IBD and HS). Patients with HS had a higher mean body mass index, a higher smoking rate, and more commonly showed cutaneous manifestations of tunnels and comedones, while fistulas, abscesses, induration, anal tags, ulcers, and anal fissures were more common in patients with IBD. In addition to having lesions in the perianal area, patients with IBD often had lesions in the buttocks and perineum, while those with HS had additional lesions in the axillae and groin. Among the statistically significant features, the 15 most important were identified by random forest: fistula, tunnel, digestive symptom, knife‐cut ulcer, perineum, body mass index, age, axilla, abscess, tags, smoking, groin, genital cutaneous edema, erythema, and bilateral/unilateral.ConclusionsThe results of this study may help differentiate perianal lesions, especially perineal HS and fistulizing perineal IBD, and provide promise for a better therapeutic outcome.
Causal relationship between folic acid and prostate cancer risk: Insights from Mendelian randomization analysis
Authors: Guo Xiaoxiao , Zhang Fengbo , Hao Gangyue 
Published: September 2024

ObjectiveFolic acid is a commonly used dietary supplement of trace element, but it may increase the risk of prostate cancer (PCa). The aim of this study was to investigate the causal relationship between PCa and folic acid supplementation, as well as dietary folate equivalents, using Mendelian randomization (MR) analysis.MethodsThe Genome‐Wide Association Study (GWAS) data of folic acid supplementation and dietary folate equivalents were selected from UK Biobank. Meta‐analysis of GWASs of PCa was obtained from PCa Association Group to Investigate Cancer‐Associated Alterations in the Genome consortium. MR analysis was performed with inverse variance weighted (IVW) method, MR‐Egger regression, simple mode, weighted median, and weighted mode analysis. Heterogeneity and horizontal pleiotropy tests and reverse MR analysis were conducted to assess the robustness and reliability of the causal inference.ResultsSix single nucleotide polymorphisms (SNPs) associated with folic acid supplementation and five SNPs associated with dietary folate equivalents were identified as instrumental variables. Genetically predicted folic acid supplementation was associated with an increased risk of PCa (OR 1.200, p < 0.001, by IVW method), and there was no evidence of heterogeneity, horizontal pleiotropy, or significant reverse causality (all p > 0.05). In contrast, dietary folate equivalents showed no significant correlation with PCa (p > 0.05 for all five MR methods).ConclusionThis study demonstrated an association between increased risk of PCa and folic acid supplementation, but not with dietary folate equivalents. These findings have implications for public health interventions and personalized preventive strategies for PCa.
Foraging in the darkness: Highly selective tuning of below‐ground larval olfaction to Brassicaceae volatiles in striped flea beetle
Authors: Xiao Yong , Lei Chunmei , Wang Xue , Batool Raufa , Yin Fei , Peng Zhengke , Jing Xiangfeng , Li Zhenyu 
Published: September 2024

AbstractThe olfactory system of above‐ground insects is among the best described perceptual architectures. However, remarkably little is known about how below‐ground insects navigate in the dark for foraging. Here, we investigated host plant preferences, olfactory sensilla and characterise olfactory proteins in below‐ground larvae of the striped flea beetle (SFB) Phyllotreta striolata Fabricius (Coleoptera: Chrysomelidae). Both the adults and larvae of this coleopteran pest cause serious damage to Brassicaceous crops above and below ground, respectively. To elucidate the role of olfactory system in host location of below‐ground larvae, we initially demonstrated that SFB larvae distinctly favoured Brassicaceae over other plant families by two‐choice behavioural bioassay. Subsequently, scanning electron microscopy of sensilla in SFB larval head showed a significant reduction in the number of olfactory sensilla in larvae compared with adults. However, essential olfactory sensilla such as sensilla basiconica are underscoring the indispensability of the larval olfactory system. We selected four larval‐specific odorant binding proteins for functional validation from our previous transcriptome data. Functional studies revealed that PstrOBP23 exhibits robust binding affinity to 24 volatiles of Brassicaceae plants, including seven isothiocyanate compounds. This suggests a pivotal role of PstrOBP23 in the foraging behaviour of the larvae below the ground. Moreover, two ligands displaying strong binding capacity exhibit apparent attractive or repellent activity towards SFB larvae. Our findings provide a crucial insight into the olfactory system of below‐ground larvae in SFB, highlighting the highly selective tuning of larvae specific OBP to host plant volatiles. These results offer potential avenues for developing effective pest control strategies against SFB.