bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling
Authors: Scarth James A. , Wasson Christopher W. , Patterson Molly R. , Evans Debra , Barba-Moreno Diego , Carden Holli , Cassidy Rosa , Whitehouse Adrian , Mankouri Jamel , Samson Adel , Morgan Ethan L. , Macdonald Andrew 
Published: July 2023

AbstractPersistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.
Changes in inflammatory proteins following platelet transfusion in a neonatal population
Authors: Moore Carmel Maria , O’Reilly Daniel , McCallion Naomi , Curley Anna E. 
Published: July 2023

Abstract
Background
Studies have demonstrated increased morbidity and mortality with platelet transfusions in the neonatal period. Platelets are as important for host immunity and inflammation as for hemostasis. Increased inflammation may explain the dose-associated increase in mortality, bleeding, and lung disease.

Objective
This study aims to assess if there are any changes in inflammatory cytokines post-platelet transfusion in babies in NICU.

Methods
This prospective observational study recruited babies due to receive a non-emergency platelet transfusion. Dried whole blood samples were collected prior to and 2 h post-transfusion. Samples were processed using multiplex immunoassay to enable analysis of tiny blood volumes. Statistical analysis was performed using R.

Results
Seventeen babies underwent 26 platelet transfusions across two centers. Median birthweight was 1545 g (535–3960 g) and median birth gestation was 31 weeks and 1 day (23 + 1 to 40 + 5). Median pre-transfusion platelet count was 19.5 × 109/l. There was a significant increase in levels of CXCL5 (p < 0.001), CD40 (p = 0.001), and TGF-β (p = 0.001) in neonatal blood samples post-platelet transfusion in the study group.

Conclusion
The increase in the cytokines CXCL5, CD40 and TGF-β after platelet transfusion in babies in NICU could potentiate existing inflammation, NEC, lung, or white matter injury. This could potentially explain long-term harm from platelet transfusion in babies.

Impact

There is a change in levels of immunomodulatory proteins CXCL5, CD40, and TGF-β after platelet transfusion in babies in NICU.

Murine neonatal models have demonstrated an increase in cytokine levels after platelet transfusions. This is the first time that this has been demonstrated in human neonates.

The increase in proinflammatory cytokines could potentially explain the long-term harm from platelet transfusion in babies, as they could potentiate existing inflammation, NEC, lung injury, or white matter injury.
Irradiation and lithium treatment alter the global DNA methylation pattern and gene expression underlying a shift from gliogenesis towards neurogenesis in human neural progenitors
Authors: Neofytou Christina , Backlund Alexandra , Blomgren Klas , Hermanson Ola 
Published: July 2023

AbstractCentral nervous system (CNS) tumors account for almost a third of pediatric cancers and are the largest contributor to cancer-related death in children. Cranial radiation therapy (CRT) is, often in combination with chemotherapy and surgery, effective in the treatment of high-grade childhood brain cancers, but it has been associated with late complications in 50–90% of survivors, such as decline in cognition and mood, decreased social competence, and fatigue. A leading hypothesis to explain the decline in cognition, at least partially, is injury to the neural stem and progenitor cells (NSPCs), which leads to apoptosis and altered fate choice, favoring gliogenesis over neurogenesis. Hence, treatments harnessing neurogenesis are of great relevance in this context. Lithium, a well-known mood stabilizer, has neuroprotective and antitumor effects and has been found to reverse irradiation-induced damage in rodents, at least in part by regulating the expression of the glutamate decarboxylase 2 gene (Gad2) via promoter demethylation in rat NSPCs. Additionally, lithium was shown to rescue irradiation-induced cognitive defects in mice. Here, we show that irradiation (IR) alone or in combination with lithium chloride (LiCl) caused major changes in gene expression and global DNA methylation in iPSC-derived human NSPCs (hNSPCs) compared to untreated cells, as well as LiCl-only-treated cells. The pattern of DNA methylation changes after IR-treatment alone was stochastic and observed across many different gene groups, whereas differences in DNA methylation after LiCl-treatment of irradiated cells were more directed to specific promoters of genes, including genes associated with neurogenesis, for example GAD2. Interestingly, IR and IR + LiCl treatment affected the promoter methylation and expression of several genes encoding factors involved in BMP signaling, including the BMP antagonist gremlin1. We propose that lithium in addition to promoting neuronal differentiation, also represses glial differentiation in hNSPCs with DNA methylation regulation being a key mechanism of action.
Methyl-CpG binding domain 2 (Mbd2) is an epigenetic regulator of autism-risk genes and cognition
Authors: Lax Elad , Do Carmo Sonia , Enuka Yehoshua , Sapozhnikov Daniel M. , Welikovitch Lindsay A. , Mahmood Niaz , Rabbani Shafaat A. , Wang Liqing , Britt Jonathan P. , Hancock Wayne W. , Yarden Yosef , Szyf Moshe 
Published: July 2023

AbstractThe Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2−/−) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2−/− mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, downregulated genes are significantly enriched for human ortholog ASD risk genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2−/− mice. These findings suggest that Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.
A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission
Authors: Nguyen Mai N. , Chakraborty Dibyendu , Rao Sriganesh Ramachandra , Onysk Agnieszka , Radkiewicz Mariusz , Surmacz Liliana , Swiezewska Ewa , Soubeyrand Eric , Akhtar Tariq A. , Kraft Timothy W. , Sherry David M. , Fliesler Steven J. , Pittler Steven J. 
Published: July 2023

AbstractRetinitis pigmentosa (RP) defines a group of hereditary progressive rod-cone degenerations that exhibit a common phenotype caused by variants in over 70 genes. While most variants in thedehydrodolichyldiphosphatesynthase (DHDDS) gene result in syndromic abnormalities, some variants cause non-syndromic RP (RP59). DHDDS encodes one subunit of the enzymecis-prenyltransferase (CPT), which is required for the synthesis of dolichol (Dol), that is a necessary protein glycosylation cofactor. We previously reported the creation and initial characterization of a knock-in (KI) mouse model harboring the most prevalent RP59-associatedDHDDSvariant (K42E) to understand how defects in DHDDS lead to retina-specific pathology. This model exhibited no profound retinal degeneration, nor proteinN-glycosylation defects. Here, we report that the Dol isoprenylogue species in retina, liver, and brain of the K42E mouse model are statistically shorter than in the corresponding tissues of age-matched controls, as reported in blood and urine of RP59 patients. Retinal transcriptome analysis demonstrated elevation of many genes encoding proteins involved in synaptogenesis and synaptic function. Quantitative retinal cell layer thickness measurements demonstrated a significant reduction in the inner nuclear layer (INL) and total retinal thickness (TRT) beginning at postnatal (PN) ∼2 months, progressively increasing to PN 18-mo. Histological analysis revealed cell loss in the INL, outer plexiform layer (OPL) disruption, and ectopic localization of outer nuclear layer (ONL) nuclei into the OPL of K42E mutant retinas, relative to controls. Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave amplitudes beginning at PN 1-mo, progressively declining through PN 18-mo, without appreciable a-wave attenuation, relative to controls. Our results suggest that the underlying cause ofDHDDSK42E variant driven RP59 retinal pathology is defective synaptic transmission from outer to inner retina.
TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells
Authors: Kitajima Hiroshi , Maruyama Reo , Niinuma Takeshi , Yamamoto Eiichiro , Takasawa Akira , Takasawa Kumi , Ishiguro Kazuya , Tsuyada Akihiro , Suzuki Ryo , Sudo Gota , Kubo Toshiyuki , Mitsuhashi Kei , Idogawa Masashi , Tange Shoichiro , Toyota Mutsumi , Yoshido Ayano , Kumegawa Kohei , Kai Masahiro , Yanagihara Kazuyoshi , Tokino Takashi , Osanai Makoto , Nakase Hiroshi , Suzuki Hiromu 
Published: July 2023

AbstractLong noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.
Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway
Authors: Yang Bin , Zhao Yunjie , Luo Wu , Zhu Weiwei , Jin Leiming , Wang Minxiu , Ye Lin , Wang Yi , Liang Guang 
Published: July 2023

AbstractObesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and may provide new therapeutic targets for this disease. Doublecortin-like kinase 1 (DCLK1) is an important target for cancer therapy and the role of DCLK1 in obesity and cardiovascular diseases is unclear. Herein, we showed that DCLK1 was overexpressed in the cardiac tissue of obese mice and investigated the role of DCLK1 in obesity-induced cardiomyopathy. We generated DCLK1-deleted mice and showed that macrophage-specific DCLK1 knockout, rather than cardiomyocyte-specific DCLK1 knockout, prevented high-fat diet (HFD)-induced heart dysfunction, cardiac hypertrophy, and fibrosis. RNA sequencing analysis showed that DCLK1 deficiency exerted cardioprotective effects by suppressing RIP2/TAK1 activation and inflammatory responses in macrophages. Upon HFD/palmitate (PA) challenge, macrophage DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release, which further promotes hypertrophy in cardiomyocytes and fibrogenesis in fibroblasts. Finally, a pharmacological inhibitor of DCLK1 significantly protects hearts in HFD-fed mice. Our study demonstrates a novel role and a pro-inflammatory mechanism of macrophage DCLK1 in obesity-induced cardiomyopathy and identifies DCLK1 as a new therapeutic target for the treatment of this disease.
Targeting Wnt/β-catenin-mediated upregulation of oncogenic NLGN3 suppresses cancer stem cells in glioblastoma
Authors: Yun Eun-Jin , Kim Donghwi , Kim Sangwoo , Hsieh Jer-Tsong , Baek Seung Tae 
Published: July 2023

AbstractGlioblastoma (GBM) is the most malignant tumor in brain and is highly resistant to therapy. Clinical evidence suggests increased number of cancer stem cells (CSCs) may contribute to the failure of conventional therapies, but the mechanisms associated with acquisition of CSC properties in GBM are not fully understood. We found that DAB2IP suppresses CSC properties by targeting the synaptic proteins neuroligin 3 (NLGN3) in GBM. Furthermore, we showed that GBM-derived NLGN3 has an oncogenic function by inducing CSC properties within GBM. Moreover, elevated NLGN3 transcription mediated by Wnt/β-catenin signaling pathway resulted in increased secretion of NLGN3 into the surrounding tumor microenvironment. Both condition media containing NLGN3 and recombinant NLGN3 transformed neighboring cells to CSCs, suggesting NLGN3 as a critical component inducing CSC properties. Furthermore, targeting NLGN3-bearing CSCs using upstream Wnt/β-catenin inhibitors synergistically enhances the efficacy of conventional treatment. Hence, we unveiled the series of regulatory mechanisms for acquisition of CSC properties in GBM progression by Wnt/β-catenin-mediated NLGN3. These results may provide a new targeting strategy to improve the therapeutic efficacy of GBM treatments.
Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination
Authors: Tong X. , McNamara R. P. , Avendaño M. J. , Serrano E. F. , García-Salum T. , Pardo-Roa C. , Bertera H. L. , Chicz T. M. , Levican J. , Poblete E. , Salinas E. , Muñoz A. , Riquelme A. , Alter G. , Medina R. A. 
Published: July 2023

AbstractSince the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.
Scalable graphene sensor array for real-time toxins monitoring in flowing water
Authors: Maity Arnab , Pu Haihui , Sui Xiaoyu , Chang Jingbo , Bottum Kai J. , Jin Bing , Zhou Guihua , Wang Yale , Lu Ganhua , Chen Junhong 
Published: July 2023

AbstractRisk management for drinking water often requires continuous monitoring of various toxins in flowing water. While they can be readily integrated with existing water infrastructure, two-dimensional (2D) electronic sensors often suffer from device-to-device variations due to the lack of an effective strategy for identifying faulty devices from preselected uniform devices based on electronic properties alone, resulting in sensor inaccuracy and thus slowing down their real-world applications. Here, we report the combination of wet transfer, impedance and noise measurements, and machine learning to facilitate the scalable nanofabrication of graphene-based field-effect transistor (GFET) sensor arrays and the efficient identification of faulty devices. Our sensors were able to perform real-time detection of heavy-metal ions (lead and mercury) and E. coli bacteria simultaneously in flowing tap water. This study offers a reliable quality control protocol to increase the potential of electronic sensors for monitoring pollutants in flowing water.
Cell-type-specific plasticity of inhibitory interneurons in the rehabilitation of auditory cortex after peripheral damage
Authors: Kumar Manoj , Handy Gregory , Kouvaros Stylianos , Zhao Yanjun , Brinson Lovisa Ljungqvist , Wei Eric , Bizup Brandon , Doiron Brent , Tzounopoulos Thanos 
Published: July 2023

AbstractPeripheral sensory organ damage leads to compensatory cortical plasticity that is associated with a remarkable recovery of cortical responses to sound. The precise mechanisms that explain how this plasticity is implemented and distributed over a diverse collection of excitatory and inhibitory cortical neurons remain unknown. After noise trauma and persistent peripheral deficits, we found recovered sound-evoked activity in mouse A1 excitatory principal neurons (PNs), parvalbumin- and vasoactive intestinal peptide-expressing neurons (PVs and VIPs), but reduced activity in somatostatin-expressing neurons (SOMs). This cell-type-specific recovery was also associated with cell-type-specific intrinsic plasticity. These findings, along with our computational modelling results, are consistent with the notion that PV plasticity contributes to PN stability, SOM plasticity allows for increased PN and PV activity, and VIP plasticity enables PN and PV recovery by inhibiting SOMs.
Aggregation-regulated room-temperature phosphorescence materials with multi-mode emission, adjustable excitation-dependence and visible-light excitation
Authors: You Jingxuan , Zhang Xin , Nan Qinying , Jin Kunfeng , Zhang Jinming , Wang Yirong , Yin Chunchun , Yang Zhiyong , Zhang Jun 
Published: July 2023

AbstractConstructing room-temperature phosphorescent materials with multiple emission and special excitation modes is fascinating and challenging for practical applications. Herein, we demonstrate a facile and general strategy to obtain ecofriendly ultralong phosphorescent materials with multi-mode emission, adjustable excitation-dependence, and visible-light excitation using a single organic component, cellulose trimellitate. Based on the regulation of the aggregation state of anionic cellulose trimellitates, such as CBtCOONa, three types of phosphorescent materials with different emission modes are fabricated, including blue, green and color-tunable phosphorescent materials with a strong excitation-dependence. The separated molecularly-dispersed CBtCOONa exhibits blue phosphorescence while the aggregated CBtCOONa emits green phosphorescence; and the CBtCOONa with a coexistence state of single molecular chains and aggregates exhibits color-tunable phosphorescence depending on the excitation wavelength. Moreover, aggregated cellulose trimellitates demonstrate unique visible-light excitation phosphorescence, which emits green or yellow phosphorescence after turning off the visible light. The aggregation-regulated phenomenon provides a simple principle for designing the proof-of-concept and on-demand phosphorescent materials by using a single organic component. Owing to their excellent processability and environmental friendliness, the aforementioned cellulose-based phosphorescent materials are demonstrated as advanced phosphorescence inks to prepare various disposable complex anticounterfeiting patterns and information codes.
Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
Authors: Morse Paul T. , Pérez-Mejías Gonzalo , Wan Junmei , Turner Alice A. , Márquez Inmaculada , Kalpage Hasini A. , Vaishnav Asmita , Zurek Matthew P. , Huettemann Philipp P. , Kim Katherine , Arroum Tasnim , De la Rosa Miguel A. , Chowdhury Dipanwita Dutta , Lee Icksoo , Brunzelle Joseph S. , Sanderson Thomas H. , Malek Moh H. , Meierhofer David , Edwards Brian F. P. , Díaz-Moreno Irene , Hüttemann Maik 
Published: July 2023

AbstractSkeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochromec(Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochromecoxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc(1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.