bluuebunny/crossref_metadata_2025_split huggingface dataset:
A combination of genomics and transcriptomics provides insights into the distribution and differential mRNA expression of type VI secretion system in clinical
Klebsiella pneumoniae
Authors: Li Wanzhen , Huang Xiaolan , Li Dan , Liu Xiaofen , Jiang Xiaoying , Bian Xingchen , Li Xin , Zhang Jing 
Published: March 2024

ABSTRACT

The type VI secretion system (T6SS) serves as a crucial molecular weapon in interbacterial competition and significantly influences the adaptability of bacteria in their ecological niche. However, the distribution and function of T6SS in clinical
Klebsiella pneumoniae
, a common opportunistic nosocomial pathogen, have not been fully elucidated. Here, we conducted a genomic analysis of 65 clinical
K. pneumoniae
isolates obtained from patients with varying infections. Genes encoding a T6SS cluster present in all analyzed strains of
K. pneumoniae,
and strains with identical sequence type carried structurally and numerically identical T6SS. Our study also highlights the importance of selecting conserved regions within essential T6SS genes for PCR-based identification of T6SS in bacteria. Afterward, we utilized the predominant sequence type 11 (ST11)
K. pneumoniae
HS11286 to investigate the effect of knocking out T6SS marker genes
hcp
or
vgrG
. Transcriptome analysis identified a total of 1,298 co-upregulated and 1,752 co-downregulated differentially expressed genes in both mutants. Pathway analysis showed that only Δ
hcp
mutant exhibited alterations in transport, establishment of localization, localization, and cell processes. The absence of
hcp
or
vgrG
gene suppressed the expression of other T6SS-related genes within the locus I cluster. Additionally, interbacterial competition experiments showed that
hcp
and
vgrG
are essential for competitive ability of ST11
K. pneumoniae
HS11286. This study furthers our understanding of the genomic characteristics of T6SS in clinical
K. pneumoniae
and suggests the involvement of multiple genes in T6SS of strain HS11286.

IMPORTANCE

Gram-negative bacteria use type VI secretion system (T6SS) to deliver effectors that interact with neighboring cells for niche advantage.
Klebsiella pneumoniae
is an opportunistic nosocomial pathogen that often carries multiple T6SS loci, the function of which has not yet been elucidated. We performed a genomic analysis of 65 clinical
K. pneumoniae
strains isolated from various sources, confirming that all strains contained T6SS. We then used transcriptomics to further study changes in gene expression and its effect on interbacterial competition following the knockout of key T6SS genes in sequence type 11 (ST11)
K. pneumoniae
HS11286. Our findings revealed the distribution and genomic characteristics of T6SS in clinical
K. pneumoniae
. This study also described the overall transcriptional changes in the predominant Chinese ST11 strain HS11286 upon deletion of crucial T6SS genes. Additionally, this work provides a reference for future research on the identification of T6SS in bacteria.
Promoting Urban Studies and Practice with Emerging Technologies: City Laboratory, New City, and Future City Exploration
Authors: Long Ying , Zhang Enjia 
Published: March 2024

The Fourth Industrial Revolution, marked by emerging/disruptive technologies like mobile internet, big data, robotics, artificial intelligence (AI), immersive media (VR/AR/MR), and the Internet of Things (IoT), is transforming cities and promoting urban development. This paper argues that these technologies foster urban studies and implementation in three pathways: methodology, epistemology, and practice. First, the new data environment offers a foundation for quantitative and objective urban studies, enabling researchers to treat cities as laboratories and conduct city experiments worldwide. Second, emerging technologies are reshaping contemporary urban life and space, promoting the update of urban theories. Third, these technologies are expected to be applied as new elements in the urban planning and design processes to create smart urban spatial forms that cater to contemporary needs. Overall, this paper highlights the potential significance of emerging technologies for urban research and development in terms of research methods and data support, theoretical updates and iterations, and practical urban planning and design.
East Barents Basin and Admiralty High Composite Tectono-Sedimentary Elements, Barents Sea
Authors: Drachev Sergey S. , Henriksen Erik , Shkarubo Sergey I. , Sobolev Peter 
Published: March 2024

The East Barents Sea includes two major tectonic elements, the East Barents Basin (EBB) and the Admiralty High, which are, in the context of the volume, characterized as composite tectono-sedimentary elements. Whereas they share some stratigraphy, their early history may differ. The EBB is a dominant structural feature of the Barents Shelf, and one of the largest and deepest sedimentary basins in the Arctic. The Admiralty High rims the EBB in the east.
The advance in understanding the East Barents Sea geology was achieved during the 1980s and 1990s mainly due to a significant amount of multichannel reflection seismic data and a number of drilled deep exploration wells. These wells tested many large anticlinal structures and made several large gas discoveries, including the giant Shtokman gas and gas condensate accumulation. In the following decades, many important geological results were published in the international and Russian literature. In this chapter we provide a summary of the geology and petroleum geology of the East Barents Sea based on published results and public-domain geological reports.
Joint Associations of Diet and Device-Measured Physical Activity with Mortality and Incident CVD and Cancer: A Prospective Analysis of the UK Biobank Study
Authors: Inan-Eroglu Elif , Ahmadi Matthew , Biswas Raaj Kishore , Ding Ding , Rezende Leandro F.M. , Lee I-Min , Giovannucci Edward L. , Stamatakis Emmanuel 
Published: March 2024

Abstract

Background:
We examined the joint associations of diet and device-measured intensity-specific physical activity (PA) with all-cause mortality (ACM), cardiovascular disease (CVD), and cancer incidence.

Methods:
We used data from 79,988 participants from the UK Biobank, a population-based prospective cohort study. Light PA (LPA), moderate-to-vigorous PA (MVPA), vigorous PA (VPA), and total PA (TPA) were measured using a wrist-worn accelerometer. Diet quality score (DQS) was based on 10 foods and ranged from 0 (unhealthiest) to 100 (healthiest) points. We derived joint PA and diet variables. Outcomes were ACM, CVD, and cancer incidence including PA, diet and adiposity-related (PDAR) cancer.

Results:
During a median follow-up of 8 years, 2,863 deaths occurred, 11,053 participants developed CVD, 7,005 developed cancer, and 3,400 developed PDAR cancer. Compared with the least favorable referent group (bottom PA tertile/low DQS), participants with middle and high (total and intensity specific) PA, except for LPA, had lower ACM risk and incident CVD risk, regardless of DQS. For example, among middle and high VPA and high DQS groups, CVD HR were 0.79 (95% CI, 0.74–0.86) and 0.75 (95% CI, 0.69–0.82), respectively. The pattern of cancer results was less pronounced but in agreement with the ACM and CVD incidence findings (e.g., HR, 0.90, 95% CI, 0.81–0.99; 0.88, 0.79–0.98; and 0.82, 0.74–0.92 among high VPA for low, moderate, and high DQS groups, respectively).

Conclusions:
Device-measured PA reveals novel joint associations with diet on health outcomes.

Impact:
Our results emphasize the crucial role of PA in addition to a healthy diet for reducing chronic diseases and mortality risk.
Abstract A045: Engineered systems for tumor modeling facilitate the assessment of theraputic interventions
Authors: Mueller Joseph , Yao Ryan , Selting Kim , Best-Popescu Catherine , Harley Brendan , Pedron-Haba Sara 
Published: March 2024

Abstract
Brain cancers remain some of the most challenging tumors to treat. The goal of our research is to use a 3D in vitro model to acquire in-depth understanding of the unique environment of brain tumors in order to find new biomarkers of disease and develop more efficient therapeutic approaches. Glioblastomas (GBM) present a very poor prognosis, they exhibit high infiltration into brain parenchyma, impairing surgical resection and leading to recurrence. The recurrent tumor is predominantly more aggressive and resistant to available therapeutic strategies. Brain extracellular matrix (ECM) plays a key role in glioblastoma invasion and therapeutic resistance. In particular, the aberrant biosynthesis of the main component of brain ECM, hyaluronic acid (HA), has been associated to pathological conditions. We investigate the influence of tumor extracellular microenvironment in glioblastoma progression. We focus on the tumor-associated HA biosynthesis in response to biophysical alterations, such as hypoxia and stiffness, and after radio and chemotherapeutic interventions. The ability to manipulate tumor ECM can improve therapeutic outcomes and restrict glioblastoma growth and infiltration.
Citation Format: Joseph Mueller, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba. Engineered systems for tumor modeling facilitate the assessment of theraputic interventions [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A045.
Abstract B014: CHD5 suppresses glioblastoma by inhibiting MYC
Authors: Sun Xueqin Sherine , Mills Alea 
Published: March 2024

Abstract
Fundamentally, cancer is a disease caused by genetic and epigenetic alterations that converge to reprogram gene expression networks, leading to unrestrained proliferation. Glioblastoma (GBM) is the most prevalent and aggressive primary brain cancer, median survival being approximately one year and the 5-year survival rate being only 5%. Despite decades of effort, this devastating picture has not appreciably improved and effective therapies have been elusive for GBM patients. A better understanding of GBM biology is essential for developing more effective therapies. Although several genetic alterations have been implicated in gliomagenesis, driving genetic factors responsible for GBM are still obscure, and the interplay between genetic alterations and epigenetic dysregulation is largely undocumented during the gliomagenic process. Here, we show that CHD5 — a gene mapping to the 1p36 chromosomal region that is notoriously deleted in many cancers, is recurrently deleted in over 20% of GBM cases and is further downregulated through epigenetic means. To delineate how CHD5 loss promotes gliomagenesis, we established a glioma-prone mouse model harboring conditional alleles of Pten, Trp53, and Chd5. We developed an engineered mouse neural stem cell (NSCs)-based strategy to elicit glioma formation, as NSCs are the major cell-of-origin for GBM. We show that Chd5 loss significantly impairs NSCs differentiation while promoting proliferation, transformation, and gliomagenesis in vivo. Mechanistically, Chd5 forms a Chd3-containing but Chd4-independent NuRD complex that directly binds the Myc promoter and super enhancers to govern Myc expression in normal NSCs, with the Snf2 domain of Chd5 playing the most critical chromatin regulating role in the context of GBM. Chd5 loss triggers the remodeling of chromatin, enhances accessibility, and augments Myc expression, leading to the formation of highly aggressive glioma. Furthermore, reactivating CHD5 in human GBM xenograft models significantly extends survival. This work demonstrates the tumor suppressive role of CHD5 in gliomagenesis, providing therapeutic insights for cancers with 1p36 deletions. In parallel, this work presents a powerful strategy for rapidly interrogating gene function during gliomagenesis using engineering NSCs and highlights the generation of novel mouse models with classic clinical features of GBM, offering new approaches for elucidating GBM biology that can inform on therapeutic opportunities for treating patients with GBM.
Citation Format: Xueqin Sherine Sun, Alea Mills. CHD5 suppresses glioblastoma by inhibiting MYC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B014.
Abstract B033: Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability
Authors: Day Charles A. , Grigore Florina , Langfald Alyssa , Hakkim Faruck , Daniels David , Vaughan Kevin , Robinson James , Hinchcliffe Edward 
Published: March 2024

Abstract
Diffuse gliomas are pediatric high-grade gliomas that frequently harbor heterozygous histone H3.3 K27M, G34R, or G34V mutations. These mutations alter histone methylations, although the precise mechanism(s) of gliomagenesis remains uncertain. H3.3 contains a unique Serine at position 31 that is phosphorylated in prophase and dephosphorylated in anaphase during normal cell division. Previously we have reported that chromosome missegregation triggers H3.3 S31 phosphorylation along chromosome arms in ana/telophase leading to p53-induced cell cycle arrest. Here we show, in vitro and in vivo, that H3.3 K27M, G34R, and G34V suppress S31 phosphorylation by its mitotic kinase, Chk1. In diploid cells, overexpression of H3.3 K27M, G34R, G34V, or non-phosphorylatable S31A significantly increases the frequency of chromosome missegregation, while H3.3 K36M did not. This missegregation phenotype could be rescued by overexpression of K27M/S31E or G34R/S31E double mutants. Next, we used CRISPR/Cas9 gene editing to revert K27M or G34V patient-derived DMG cells to WT or replace the mutant allele with S31A. Reversion to WT increased metaphase S31 phosphorylation and reduced chromosome missegregations, but inserting an S31A mutation caused more mitotic defects. Following a mitotic error, newly formed aneuploid cells overexpressing K27M, G34R, or G34V suppress p53 levels and continue to divide, while WT overexpressing cells always arrest. To test the effects of diminished S31 phosphorylation on gliomagenesis, we utilized a novel mouse model of glioma. Expression of PDGFß linked to H3.3K27M, H3.3G34R, and H3.3S31A in neural stem cells in vivo promoted the development of high-grade gliomas in under 100 days, whereas PDFß-H3.3WT did not. Notably, the S31A tumors had histologically normal levels of K27me3 and K36me3. This work shows that a single glioma-associated point mutation in H3.3 can generate chromosomal instability, and which is a major contributing factor to H3.3 K27M and G34-altered glioma formation.
Citation Format: Charles A. Day, Florina Grigore, Alyssa Langfald, Faruck Hakkim, David Daniels, Kevin Vaughan, James Robinson, Edward Hinchcliffe. Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B033.
Abstract B052: Hyaluronic acid influences amino acid metabolism in glioblastoma's U87-MG cell line in a 2D culture via LAT1 transporter expression
Authors: Bale Ashwin A. , Bhargava Rohit , Harley Brendan 
Published: March 2024

Abstract
Glioblastoma (GBM) is one of the deadliest forms of brain cancer with high inter and intra tumor heterogeneity and altered metabolism pathways. GBM’s microenvironment is highly complex and plays a key role in determining overall tumor growth and patient survival. Hyaluronic acid (HA) is one of the key components of this tumor microenvironment and is often associated with poor prognosis. HA is present in the form of polymeric chain units, and it is highly likely that the resulting molecular weight (MW) distribution influences how a tumor cell behaves. Through this study, we highlight this differential influence of HA MWs on GBM’s energy metabolism. GBM’s U87-MG cell lines were grown in an adherent culture with media supplemented with different MWs of HA (10, 60 and 500 kDa) and glucose concentrations (0 mM: glucose starved, 5.5 mM: normoglycemic and 25 mM: hyperglycemic). LC-MS analysis on supernatant media coupled with numerical analysis highlighted an interesting influence of HA on GBM’s amino acid metabolism via reduction in LAT1 transporter protein expression. The results also indicated a differential influence on mitochondrial respiration levels with changing ATP demands and a difference in the accumulation of some key products of cell fermentation (lactic acid, glutamic acid, and succinic acid). Overall, these results highlight the differential influence of HA MWs on the metabolic state of GBM.
Citation Format: Ashwin A. Bale, Rohit Bhargava, Brendan Harley. Hyaluronic acid influences amino acid metabolism in glioblastoma's U87-MG cell line in a 2D culture via LAT1 transporter expression [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B052.
Abstract A006: Loss of XIST induces tumor metabolism reprogramming in ovarian cancer
Authors: Naciri Ikrame , Liang Minzhi , Yang Ying , Andrade Ludena Maria De Lourdes , Karner Heather , Lin Benjamin , Lebron Alfredo , Kong Mei , Sun Sha 
Published: March 2024

Abstract
Long noncoding RNAs (lncRNAs) have emerged as key players in various physiological processes, with dysregulation linked to diseases such as cancer. As diagnostic markers and therapeutic targets, lncRNAs have attracted considerable interest in cancer biology. XIST is one of the most studied lncRNAs, known as the master regulator of X chromosome inactivation (XCI) in mammals. The molecular mechanisms and regulatory elements of XCI have been extensively studied. However, their role in cancer susceptibility, particularly in female cancers, and their alterations in cancer cells remain elusive. To gain insight into the role of XIST in ovarian cancer, we analyzed TCGA ovarian cancer data and observed a downregulation of XIST expression in patients with high-grade ovarian cancer. In subsequent experiments, we performed CRISPR Cas9 inhibition (CRISPRi) to efficiently downregulate XIST expression in two ovarian cancer cell lines, OVCAR3 and SKOV3. Our functional and transcriptional analyses revealed a surprising finding: XIST downregulation did not result in widespread reactivation of X chromosome genes; however, we found an enrichment of gene related to oxidative phosphorylation pathway (OXPHO) in our cells with XIST knockdown. This finding was validated through measurement of the oxygen consumption rate, an indicator of OXPHO, which was higher in cells with downregulated XIST. In addition, we examined sequencing data from ovarian cancer patient samples and found that patients with low XIST expression showed an enrichment of genes related to oxidative phosphorylation, in accordance with our in vitro data. Under hypoxic stress, this metabolic shift resulted in increased colony formation and enhanced proliferation of ovarian cancer cells. Preliminary results from our xenograft experiments indicate enhanced tumor development with XIST-low cancer cells. Overall, our findings provide insight into the potential tumor suppressor role of XIST in ovarian cancer. Our study presents novel evidence implicating the XIST lncRNA in the metabolic oxidative phosphorylation pathway, thereby opening up the possibility of targeting this pathway for ovarian cancer patients with low XIST expression.
Citation Format: Ikrame Naciri, Minzhi Liang, Ying Yang, Maria De Lourdes Andrade Ludena, Heather Karner, Benjamin Lin, Alfredo Lebron, Mei Kong, Sha Sun. Loss of XIST induces tumor metabolism reprogramming in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A006.
Abstract A026: Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer
Authors: Peplinski Rebekah M. , Nobre Silvana Pedra , Schillo Jacob L. , Ulmer Keely K. , Lyons Yasmin A. , Riordan Jesse D. , Goodheart Michael J. , Dupuy Adam J. 
Published: March 2024

Abstract
Low-grade serous ovarian cancer (LGSOC) has recently been characterized as a unique subtype of ovarian cancer with distinct molecular characteristics, clinical treatments, and therapeutic responses. Although LGSOC accounts for ~5% of ovarian cancers, the age of onset is younger (~45 years) than other subtypes and has a low response rate (~4%) to the standard of care chemotherapy. One defining characteristic of LGSOC is frequent genetic alterations in the MAPK pathway, which has led to recent MAPK-targeted therapeutic clinical trials. MEK inhibition, particularly with trametinib, has been shown to be effective in patients with recurrent LGSOC (Phase II/III Trial: GOG 281/LOGS). However, these patients eventually develop therapeutic resistance and progressive disease, with no remaining treatment options. Here we sought to characterize the biology of LGSOC and its response to trametinib in an effort to identify candidate mechanisms that may be targeted in combination with trametinib to improve therapeutic efficacy and outcomes for LGSOC patients. After characterizing trametinib responses and identifying cytotoxic doses for a panel of LGSOC cell lines (ES2, OVCAR8, VOA7681, OV7, and OV56), we performed RNA sequencing on each cell line under basal conditions, as well as after 24-hour or 7-day exposure to an IC95 dose of trametinib. These experiments identified both acute and longer-term transcriptional changes that occur in response to trametinib. CRISPR screens targeting the kinome were also performed to identify synthetic lethal interactions between trametinib treatment and loss of function of specific protein kinases. Integrated analysis of these approaches identified several potential candidates (AKT, mTOR, CDKs, among others) that may be targeted in combination with trametinib to improve LGSOC patient outcomes. Experiments testing synergistic relationships between trametinib and other FDA approved inhibitors were performed. Using these combination therapeutic approaches could re-sensitize cells to trametinib treatment or prevent the emergence of resistance, thereby improving therapeutic efficacy. If successful, a similar approach could be used in a clinical trial to treat patients with LGSOC.
Citation Format: Rebekah M. Peplinski, Silvana Pedra Nobre, Jacob L. Schillo, Keely K. Ulmer, Yasmin A. Lyons, Jesse D. Riordan, Michael J. Goodheart, Adam J. Dupuy. Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A026.