tbuckley/cabot-search huggingface dataset:
Cis-regulatory control of transcriptional timing and noise in response to estrogen
Authors: Matthew Ginley-Hidinger, Hosiana Abewe, Kyle Osborne, Alexandra Richey, Noel Kitchen, Katelyn L. Mortenson, Erin M. Wissink, John Lis, Xiaoyang Zhang, Jason Gertz
Journal: Cell Genomics (2024)

Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single-cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We found that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.
Understanding the potential role of whole genome sequencing (WGS) in managing patients with gonorrhoea: A systematic review of WGS use on human pathogens in individual patient care
Authors: Roeann Osman, Emily Dema, Alexandra David, Gwenda Hughes, Nigel Field, Michelle Cole, Xavier Didelot, John Saunders
Journal: Journal of Infection (2024)

ObjectivesThe utility of whole genome sequencing (WGS) to inform sexually transmitted infection (STI) patient management is unclear. Timely WGS data might support clinical management of STIs by characterising epidemiological links and antimicrobial resistance profiles. We conducted a systematic review of clinical application of WGS to any human pathogen that may be transposable to gonorrhoea.MethodsWe searched six databases for articles published between 01/01/2010-06/02/2023 that reported on real/near real-time human pathogen WGS to inform clinical intervention. All article types from all settings were included. Findings were analysed using narrative synthesis.ResultsWe identified 12,179 articles, of which eight reported applications to inform tuberculosis (n=7) and gonorrhoea (n=1) clinical patient management. WGS data were successfully used as an adjunct to clinical and epidemiological data to enhance contact-tracing (n=2), inform antimicrobial therapy (n=5) and identify cross-contamination (n=1). WGS identified gonorrhoea transmission chains that were not established via partner notification. Future applications could include insights into pathogen exposure detected within sexual networks for targeted patient management.ConclusionsWhile there was some evidence of WGS use to provide individualised tuberculosis and gonorrhoea treatment, the eight identified studies contained few participants. Future research should focus on testing WGS intervention effectiveness and examining ethical considerations of STI WGS use.
LncRNA ZFPM2-AS1 promotes phyllodes tumor progression by binding to CDC42 and inhibiting STAT1 activation
Authors: Shishi He, Guowei Huang, Rong Lei, Rurong Jia, Zhanghai He, Jiewen Chen, Hongyan Huang, Zixian Huang, Ailifeire Yilihamu, Xun Li, Zilin Zhuang, Mengjia Han, Xueman Chen, Di Huang, Yan Nie
Journal: Acta Pharmaceutica Sinica B (2024)

Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro. Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo. Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.
Unlocking T cell exhaustion: Insights and implications for CAR-T cell therapy
Authors: Dian Xiong, Haijun Yu, Zhi-Jun Sun
Journal: Acta Pharmaceutica Sinica B (2024)

Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.
A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice
Authors: Ellen L. Risemberg, Johanna M. Smeekens, Marta C. Cruz Cisneros, Brea K. Hampton, Pablo Hock, Colton L. Linnertz, Darla R. Miller, Kelly Orgel, Ginger D. Shaw, Fernando Pardo Manuel de Villena, A. Wesley Burks, William Valdar, Michael D. Kulis, Martin T. Ferris
Journal: Journal of Allergy and Clinical Immunology (2024)
Molecular rapid diagnostic testing for bloodstream infections: Nanopore targeted sequencing with pathogen-specific primers
Authors: Dongsheng Han, Fei Yu, Dan Zhang, Juan Hu, Xuan Zhang, Dairong Xiang, Bin Lou, Yu Chen, Shufa Zheng
Journal: Journal of Infection (2024)

BackgroundNanopore sequencing, known for real-time analysis, shows promise for rapid clinical infection diagnosis but lacks effective assays for bloodstream infections (BSIs).MethodsWe prospectively assessed the performance of a novel nanopore targeted sequencing (NTS) assay in identifying pathogens and predicting antibiotic resistance in BSIs, analyzing 387 blood samples from December 2021 to April 2023.ResultsThe positivity rate for NTS (69.5%, 269/387) nearly matches that of metagenomic next-generation sequencing (mNGS) (74.7%, 289/387; p=0.128) and surpasses the positivity rate of conventional blood culture (BC) (33.9%, 131/387; p<0.01). Frequent pathogens detected by NTS included Klebsiella pneumoniae (n=54), Pseudomonas aeruginosa (n=36), Escherichia coli (n=36), Enterococcus faecium(n=30), Acinetobacter baumannii(n=26), Staphylococcus aureus(n=23), and Human cytomegalovirus (n=37). Against a composite BSI diagnostic standard, NTS demonstrated a sensitivity and specificity of 84.0% (95% CI 79.5%-87.7%) and 90.1% (95% CI 81.7%-88.5%), respectively. The concordance between NTS and mNGS results (the percentage of total cases where both either detected BSI-related pathogens or were both negative) was 90.2% (359/387), whereas the consistency between NTS and BC was only 60.2% (233/387). In 80.6% (50/62) of the samples with identical pathogens identified by both NTS tests and BCs, the genotypic resistance identified by NTS correlated with culture-confirmed phenotypic resistance. Using NTS, 95% of samples can be tested and analyzed in approximately 7 hours, allowing for early patient diagnosis.ConclusionsNTS is rapid, sensitive, and efficient for detecting BSIs and drug-resistant genes, making it a potential preferred diagnostic tool for early infection identification in critically ill patients.
KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2
Authors: Chaofan Peng, Peng Yang, Dongsheng Zhang, Chi Jin, Wen Peng, Tuo Wang, Qingyang Sun, Zhihao Chen, Yifei Feng, Yueming Sun
Journal: Acta Pharmaceutica Sinica B (2024)

Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.
Preoperative Left Atrial Strain Predicts Outcome in Patients With Hypertrophic Obstructive Cardiomyopathy after Myectomy
Authors: Shujuan Yang, Changsheng Zhu, Jiaxin Wang, Lele Liu, Changcheng Li, Xiuyu Chen, Kankan Zhao, Minjie Lu, Shuiyun Wang, Shihua Zhao
Journal: JACC. Cardiovascular imaging (2024)
Validation of Noninvasive Left Atrial Stiffness Against Left Atrial Operating Chamber Stiffness by Cardiac Catheterization
Authors: Isadora Sande Mathias, Wissam Rahi, Alexandra Ramos, Jonathan Na, Clara Angulo, Peter Rothstein, Adi Lador, Paul Schurmann, Amish Dave, Miguel Valderrabano, Sherif F. Nagueh
Journal: JACC. Cardiovascular imaging (2024)
Relationship Between Myocardial NPPB Expression and Serum NT-proBNP in Heart Failure With Preserved Ejection Fraction
Authors: Virginia S. Hahn, Hildur Knutsdottir, Tess E. Peterson, Daniel Kikuchi, Soumya Vungarala, David A. Kass, Kavita Sharma
Journal: JACC Heart Failure (2024)
Dramatic Disappearance of Keratic Precipitates
Authors: Arnav Panigrahi, Shikha Gupta, Viney Gupta
Journal: Ophthalmology (2024)

A 32-year-old man presented with bilateral granulomatous uveitis with intraocular pressure of 40 mmHg, and a total optic nerve cupping in both eyes. He underwent trabeculectomy in the right eye followed by the left eye. The patient had multiple keratic precipitates in both eyes (A), which had completely disappeared when his bandage was removed the day after surgery (B). We believe such a dramatic disappearance could be explained by the formation of an alternate conduit for aqueous drainage and the turbulence of the aqueous outflow, induced by the trabeculectomy ostium, facilitating quick removal of inflammatory debris along with the keratic precipitates. (Magnified version of Figure A-B is available online at www.aaojournal.org).
Hollow Globe after Traumatic Cornea Transplant Dehiscence
Authors: Sofia De Arrigunaga, Menachem Weiss, Humberto Salazar
Journal: Ophthalmology (2024)

An 82-year-old woman presented with blunt trauma to her right eye. She had a history of Baerveldt glaucoma tube shunt, anterior chamber intraocular lens (IOL), penetrating keratoplasty (PK), and no vitrectomy. Examination revealed dehisced PK in fornix (A, arrow), loss of IOL, complete vitreous loss, unaided view of optic nerve, attached retina (B), and shallow choroidal effusion. Healon (C) and balanced saline solution were poured into the globe followed by intravitreal doses of vancomycin and ceftazidime. The graft was repositioned with cyanoacrylate glue and covered with a contact lens and eye shield. Repeat PK was performed within 24 hours without complication. (Magnified version of Figure A-C is available online at www.aaojournal.org).
Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study
Authors: Isaac Allen, Hend Hassan, Walburga Yvonne Joko-Fru, Catherine Huntley, Lucy Loong, Tameera Rahman, Bethany Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Katrina Lavelle, Fiona McRonald, Diana Eccles, Eva J.A Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou
Journal: The Lancet Regional Health - Europe (2024)

BackgroundSecond primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets.MethodsThe cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan–Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression.FindingsBoth genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99–2.06) females; 55.4 (35.5–82.4) males) and non-breast (1.10 (1.09–1.11) females, 1.10 (1.00–1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31–1.38) <50 y, 1.07 (1.06–1.09) ≥50 y) and more socioeconomically deprived (SIR: 1.00 (0.98–1.02) least deprived quintile, 1.34 (1.30–1.37) most).InterpretationEnhanced SPC surveillance may benefit BC survivors, although specific recommendations require more detailed multifactorial risk and cost-benefit analyses. The associations between deprivation and SPC risks could provide clinical management insights.FundingCRUK Catalyst Award CanGene-CanVar (C61296/A27223). Cancer Research UK grant: PPRPGM-Nov 20∖100,002. This work was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Younger unrelated donors may be preferable over HLA match in the PTCy era: a study from the ALWP of the EBMT
Authors: Jaime Sanz, Myriam Labopin, Goda Choi, Alexander Kulagin, Jacopo Peccatori, Jan Vydra, Peter Pal Remenyi, Jurjen Versluis, Montserrat Rovira, Didier Blaise, Helene Labussiere-Wallet, JUAN MONTORO, Simona Sica, Ellen Meijer, Maija Itälä-Remes, Nicolaas Schaap, Claude-Eric BULABOIS, Simona Piemontese, Mohamad Mohty, Fabio Ciceri
Journal: Blood (2024)
Gasdermin E-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation
Authors: Yingfei Li, Yi He, Fangyuan Yang, Rongmei Liang, Wenchao Xu, Yehao Li, Jingbo Cheng, Baozhu Liang, Ming Tang, Xingliang Shi, Jian Zhuang, Minshuang Luo, Liuying Li, Ruilin Zhang, Huijuan Liu, Hongyu Jie, Xing Li, Xinai Han, Erwei Sun, Zeqing Zhai
Journal: British Journal of Dermatology (2024)

Psoriasis is a common chronic inflammatory disease with an unclear aetiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death.
Planned oocyte cryopreservation: a systematic review and meta-regression analysis
Authors: Ayala Hirsch, Bruria Hirsh Raccah, Reut Rotem, Jordana H Hyman, Ido Ben-Ami, Avi Tsafrir
Journal: Human Reproduction Update (2024)

Abstract BACKGROUND Awareness of the age-related decline in fertility potential has increased the popularity of planned oocyte cryopreservation (POC). However, data regarding outcomes of POC, including rates of women returning to thaw oocytes, as well as pregnancy and live birth rates, are scarce and based mostly on small case series. OBJECTIVE AND RATIONALE POC was defined as cryopreservation exclusively for prevention of future age-related fertility loss. The primary outcome was live birth rate per patient. The secondary outcomes included the return to thaw rate and laboratory outcomes. A meta-regression analysis examining the association between live birth and age above 40 or below 35 was conducted. SEARCH METHODS We conducted a systematic database search from inception to August 2022. The search included PubMed (MEDLINE) and EMBASE. Our search strategies employed a combination of index terms (Mesh) and free text words to compile relevant concepts. The systematic review and meta-regression were undertaken following registration of systematic review (PROSPERO registration number CRD42022361791) and were reported following guidelines of Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 (PRISMA 2020). OUTCOMES The database search yielded 3847 records. After the selection process, 10 studies, conducted from 1999 to 2020, were included. Overall, 8750 women underwent POC, with a mean cryopreservation age of 37.2 (±0.8). Of those, 1517 women returned to use their oocytes with a return rate of 11.1% (± 4.7%). The mean age at the time of cryopreservation for women who returned to use their oocytes was 38.1 (±0.4), with an average of 12.6 (±3.6) cryopreserved oocytes per woman. In a meta-analysis, the oocyte survival rate was 78.5% with a 95% CI of 0.74–0.83 (I2 = 93%). The live birth rate per patient was 28% with a 95% CI of 0.24–0.33 (I2 = 92%). Overall, 447 live births were reported. In a sub-group analysis, women who underwent cryopreservation at age ≥40 achieved a live birth rate per patient of 19% (95% CI 0.13–0.29, I2 = 6%), while women aged ≤35 years old or younger had a higher live birth rate per patient of 52% (95% CI 0.41–0.63, I2 = 7%). WIDER IMPLICATIONS POC emerges as a feasible option for women aiming to improve their chances of conceiving at a later reproductive age. Nonetheless, it must be acknowledged that the overall success rates of POC are limited and that the likelihood of successful live birth declines as the age at cryopreservation rises. With increasing interest in POC, the collation of comprehensive and high-quality data is imperative to clearly define the outcomes for various age groups. REGISTRATION NUMBER CRD42022361791.
Anticoagulants is a risk factor for delayed bleeding after colorectal endoscopic submucosal dissection: A HASID multicenter study
Authors: S. J. Kim, J. Lee, H. Y. Song, G. S. Seo, B. C. Jin, D. H. Kim, H. S. Kim, S. W. Kim, H. H. Oh, D. S. Myung, Y. E. Joo
Journal: Endoscopy (2024)
What is the pandemic potential of avian influenza A(H5N1)?
Authors: None The Lancet Infectious Diseases
Journal: The Lancet Infectious Diseases (2024)

On March 25, 2024, a national authority in Viet Nam notified WHO of a case of human infection with highly pathogenic avian influenza (HPAI) A(H5N1) virus (clade unreported). Then on April 1, a second but unrelated human infection with HPAI A(H5N1) virus (clade 2.3.4.4b) was reported in Texas, USA. The two cases occurred under different circumstances with different outcomes. The case in Viet Nam followed exposure to infected birds and resulted in death. By contrast, the case in Texas was in a worker on a commercial dairy farm who presented with only mild illness and was treated outside hospital.
STMP and PVPA as Templating Analogs of Noncollagenous Proteins Induce Intrafibrillar Mineralization of Type I Collagen via PCCP Process
Authors: Yiru Wang, Yizhou Zhang, Zhe Shen, Yuan Qiu, Chaoyang Wang, Zhifang Wu, Minjuan Shen, Changyu Shao, Ruikang Tang, Matthias Hannig, Baiping Fu, Zihuai Zhou
Journal: Advanced Healthcare Materials (2024)

The phosphorylated noncollagenous proteins (NCPs) play a vital role in manipulating biomineralization, while the mechanism of phosphorylation of NCPs in intrafibrillar mineralization of collagen fibril has not been completely deciphered. Poly(vinylphosphonic acid) (PVPA) and sodium trimetaphosphate (STMP) as templating analogs of NCPs induce hierarchical mineralization in cooperation with indispensable sequestration analogs such as polyacrylic acid (PAA) via polymer-induced liquid-like precursor (PILP) process. Herein, STMP-Ca and PVPA-Ca complexes are proposed to achieve rapid intrafibrillar mineralization through polyelectrolyte-Ca complexes pre-precursor (PCCP) process. This strategy is further verified effectively for remineralization of demineralized dentin matrix both in vitro and in vivo. Although STMP micromolecule fails to stabilize amorphous calcium phosphate (ACP) precursor, STMP-Ca complexes facilely permeate into intrafibrillar interstices and trigger phase transition of ACP to hydroxyapatite within collagen. In contrast, PVPA-stabilized ACP precursors lack liquid-like characteristic and crystallize outside collagen due to rigid conformation of PVPA macromolecule, while PVPA-Ca complexes infiltrate into partial intrafibrillar intervals under electrostatic attraction and osmotic pressure as evidenced by intuitionistic 3D stochastic optical reconstruction microscopy (3D-STORM). The study not only extends the variety and size range of polyelectrolyte for PCCP process but also sheds light on the role of phosphorylation for NCPs in biomineralization.
Genomic variation in weedy and cultivated broomcorn millet accessions uncovers the genetic architecture of agronomic traits
Authors: Qiong Lu, Hainan Zhao, Zhengquan Zhang, Yuhe Bai, Haiming Zhao, Guoqing Liu, Minxuan Liu, Yunxiao Zheng, Haiyue Zhao, Huihui Gong, Lingwei Chen, Xizhen Deng, Xiangde Hong, Tianxiang Liu, Baichuan Li, Ping Lu, Feng Wen, Lun Wang, Zhijiang Li, Hai Li, Haiquan Li, Like Zhang, Wenhui Ma, Chunqing Liu, Yan Bai, Beibei Xin, Jian Chen, Lizhu E, Jinsheng Lai, Weibin Song
Journal: Nature Genetics (2024)
Adaptive immune changes associate with clinical progression of Alzheimer’s disease
Authors: Lynn van Olst, Alwin Kamermans, Sem Halters, Susanne M A van der Pol, Ernesto Rodriguez, Inge M W Verberk, Sanne G S Verberk, Danielle W R Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J Garcia-Vallejo, Afina W Lemstra, Maarten E Witte, Wiesje M van der Flier, Charlotte E Teunissen, Helga E de Vries
Journal: Molecular Neurodegeneration (2024)

Abstract Background Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1 + CD57 + CD8 + T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.