bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant ventral dentate gyrus structure and function in trauma susceptible mice
Authors: Dirven Bart C. J. , van der Geugten Dewi , Temporão Carolina , van Bodegom Miranda , Madder Leonie , van Agen Laura , Homberg Judith R. , Kozicz Tamas , Henckens Marloes J.A.G. 
Published: December 2022

AbstractPost-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in trauma susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we hypothesized that susceptibility to develop PTSD-like symptoms following trauma will be underpinned by aberrant DG structure and function. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD-like symptomatology following recovery. In four independent experiments, DG neuronal morphology, synaptic protein gene and protein expression, and neuronal activity during trauma encoding and recall were assessed. Behaviorally, trauma-susceptible animals displayed increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of trauma susceptible vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer1b/c gene and protein, a larger population of neurons active during trauma encoding, and a greater presence of somatostatin neurons. In contrast, the dorsal DG of trauma-susceptible animals did not differ in terms of spine density or gene expression but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. Collectively, we here report on specific structural and functional changes in the ventral DG in trauma susceptible male mice.
Second- and third-line treatment strategies in multiple myeloma: a referral-center experience
Authors: Goldman-Mazur Sarah , Visram Alissa , Rajkumar S. Vincent , Kapoor Prashant , Dispenzieri Angela , Lacy Martha Q. , Gertz Morie A. , Buadi Francis K. , Hayman Suzanne R. , Dingli David , Kourelis Taxiarchis , Gonsalves Wilson , Warsame Rahma , Muchtar Eli , Leung Nelson , Kyle Robert A. , Kumar Shaji K. 
Published: December 2022

AbstractThe treatment landscape for relapsed multiple myeloma (MM) has increased. In this study, we aimed to characterize 2nd (n = 1439) and 3rd (n = 1104) line regimens and compare the results between subgroups based on the year of treatment initiation (2nd line: 2003–2008, 2009–2015, 2016–2021; 3rd line: 2004–2009, 2010–2015, and 2016–2021). In both the second- and third- lines, we observed increasing use of novel agents (from 78 to 95% and from 77 to 95%, respectively) and triplet regimens (from 15 to 69% and from 21 to 71%, respectively). The most frequently used regimens in the last studied periods included lenalidomide-dexamethasone (RD; 14%), carfilzomib-RD (12%), and daratumumab-RD (10%) for the second-line, and daratumumab-pomalidomide-dexamethasone (11%) and daratumumab-RD (10%) for the third-line. The median time to the next treatment from second-line therapy has improved from 10.4 months (95% CI: 8.4–12.4) to 16.6 months (95% CI: 13.3–20.3; p < 0.001). The median overall survival from the first relapse increased from 30.9 months (95% CI: 26.8–183.0) to 65.8 months (95% CI: 50.7–72.8; p < 0.001). Over the last two decades, more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and survival after the first relapse is continually improving.
RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling
Authors: Niu Zhiguo , Fan Jianing , Chen Fengzhe , Yang Huijie , Li Xin , Zhuang Ting , Guo Chunlei , Cao Qi , Zhu Jian , Wang Hui , Huang Qingsong 
Published: December 2022

AbstractBreast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.
Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo
Authors: Zhu Yinsong , Yue Peibin , Dickinson Cody F. , Yang Justin K. , Datanagan Kyrstin , Zhai Ning , Zhang Yi , Miklossy Gabriella , Lopez-Tapia Francisco , Tius Marcus A. , Turkson James 
Published: December 2022

AbstractDysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.
Bacterial protein MakA causes suppression of tumour cell proliferation via inhibition of PIP5K1α/Akt signalling
Authors: Toh Eric , Baryalai Palwasha , Nadeem Aftab , Aung Kyaw Min , Chen Sa , Persson Karina , Persson Jenny L. , Uhlin Bernt Eric , Wai Sun Nyunt 
Published: December 2022

AbstractRecently, we demonstrated that a novel bacterial cytotoxin, the protein MakA which is released by Vibrio cholerae, is a virulence factor, causing killing of Caenorhabditis elegans when the worms are grazing on the bacteria. Studies with mammalian cell cultures in vitro indicated that MakA could affect eukaryotic cell signalling pathways involved in lipid biosynthesis. MakA treatment of colon cancer cells in vitro caused inhibition of growth and loss of cell viability. These findings prompted us to investigate possible signalling pathways that could be targets of the MakA-mediated inhibition of tumour cell proliferation. Initial in vivo studies with MakA producing V. cholerae and C. elegans suggested that the MakA protein might target the PIP5K1α phospholipid-signalling pathway in the worms. Intriguingly, MakA was then found to inhibit the PIP5K1α lipid-signalling pathway in cancer cells, resulting in a decrease in PIP5K1α and pAkt expression. Further analyses revealed that MakA inhibited cyclin-dependent kinase 1 (CDK1) and induced p27 expression, resulting in G2/M cell cycle arrest. Moreover, MakA induced downregulation of Ki67 and cyclin D1, which led to inhibition of cell proliferation. This is the first report about a bacterial protein that may target signalling involving the cancer cell lipid modulator PIP5K1α in colon cancer cells, implying an anti-cancer effect.
The chromatin remodeler CHD6 promotes colorectal cancer development by regulating TMEM65-mediated mitochondrial dynamics via EGF and Wnt signaling
Authors: Zhang Boyu , Liu Qingxin , Wen Weijie , Gao Han , Wei Wenxia , Tang Aiwen , Qin Baifu , Lyu Haiwen , Meng Xiangqi , Li Kai , Jin Huilin , Yu Fenghai , Pan Qihao , Lin Junzhong , Lee Mong-Hong 
Published: December 2022

AbstractChromodomain helicase DNA binding protein (CHD) family plays critical roles in regulating gene transcription. The family is linked to cancer disease, but the family member’s role in tumorigenesis remains largely unknown. Here, we report that CHD6 is highly expressed in colorectal cancer (CRC). CHD6 knockdown inhibited cancer cell proliferation, migration, invasion, and tumorigenesis. Consistently, Villin-specific Chd6 knockout in mice attenuates cancer formation in AOM/DSS model. We found that aberrant EGF signals promoted the stability of CHD6 by diminishing ubiquitin-mediated degradation. EGF signal inhibits GSK3β activity, which in turn prevents phosphodegron formation of CHD6, thereby hindering E3 ligase FBXW7-mediated CHD6 ubiquitination and degradation. CHD6’s chromatin remodeler activity engages in binding Wnt signaling transcription factor TCF4 to facilitate the transcriptional expression of TMEM65, a mitochondrial inner membrane protein involved in ATP production and mitochondrial dynamics. In addition, Wnt signaling is also an upstream regulator of CHD6. CHD6 promoter contains TCF4 and β-catenin binding site, and CHD6 can be transcriptionally activated by Wnt ligand to facilitate TMEM65 transcription. Thus CHD6-TMEM65 axis can be regulated by both EGF and Wnt signaling pathways through two different mechanisms. We further illustrate that CHD6-TMEM65 axis is deregulated in cancer and that co-administration of Wnt inhibitor LGK974 and the anti-EGFR monoclonal antibody cetuximab largely restricted the growth of patient-derived xenografts of CRC. Targeting CHD6-TMEM65 axis may be effective for cancer intervention.
Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing
Authors: Hocking Lynne J. , Andrews Claire , Armstrong Christine , Ansari Morad , Baty David , Berg Jonathan , Bradley Therese , Clark Caroline , Diamond Austin , Doherty Jill , Lampe Anne , McGowan Ruth , Moore David J. , O’Sullivan Dawn , Purvis Andrew , Santoyo-Lopez Javier , Westwood Paul , Abbott Michael , Williams Nicola ,   Scottish Genomes Partnership, Aitman Timothy J. , Biankin Andrew V. , Cooke Susanna L. , Humphrey Wendy Inglis , Martin Sancha , Meynert Alison , Murphy Fiona , Nourse Craig , Semple Colin A. , Williams Nicola , Dean John , Foley Patricia , Robertson Lisa , Ross Alison , Williamson Karen , Berg Jonathan , Goudie David , McWilliam Catherine , Fitzpatrick David , Fletcher Elaine , Jackson Andrew , Lam Wayne , Porteous Mary , Barr Kate , Bradshaw Nicola , Davidson Rosemarie , Gardiner Carol , Gorrie Jennifer , Hague Rosie , Hamilton Mark , Joss Shelagh , Kinning Esther , Longman Cheryl , Martin Neil , McGowan Ruth , Paterson Jenny , Pilz Daniela , Snadden Lesley , Tobias Edward , Wedderburn Sarah , Whiteford Margo , Aitman Timothy J. , Miedzybrodzka Zosia 
Published: December 2022

AbstractNHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.
New globally distributed bacterial phyla within the FCB superphylum
Authors: Gong Xianzhe , del Río Álvaro Rodríguez , Xu Le , Chen Zhiyi , Langwig Marguerite V. , Su Lei , Sun Mingxue , Huerta-Cepas Jaime , De Anda Valerie , Baker Brett J. 
Published: December 2022

AbstractMicrobes in marine sediments play crucial roles in global carbon and nutrient cycling. However, our understanding of microbial diversity and physiology on the ocean floor is limited. Here, we use phylogenomic analyses of thousands of metagenome-assembled genomes (MAGs) from coastal and deep-sea sediments to identify 55 MAGs that are phylogenetically distinct from previously described bacterial phyla. We propose that these MAGs belong to 4 novel bacterial phyla (Blakebacterota, Orphanbacterota, Arandabacterota, and Joyebacterota) and a previously proposed phylum (AABM5-125-24), all of them within the FCB superphylum. Comparison of their rRNA genes with public databases reveals that these phyla are globally distributed in different habitats, including marine, freshwater, and terrestrial environments. Genomic analyses suggest these organisms are capable of mediating key steps in sedimentary biogeochemistry, including anaerobic degradation of polysaccharides and proteins, and respiration of sulfur and nitrogen. Interestingly, these genomes code for an unusually high proportion (~9% on average, up to 20% per genome) of protein families lacking representatives in public databases. Genes encoding hundreds of these protein families colocalize with genes predicted to be involved in sulfur reduction, nitrogen cycling, energy conservation, and degradation of organic compounds. Our findings advance our understanding of bacterial diversity, the ecological roles of these bacteria, and potential links between novel gene families and metabolic processes in the oceans.
Ruminant inner ear shape records 35 million years of neutral evolution
Authors: Mennecart Bastien , Dziomber Laura , Aiglstorfer Manuela , Bibi Faysal , DeMiguel Daniel , Fujita Masaki , Kubo Mugino O. , Laurens Flavie , Meng Jin , Métais Grégoire , Müller Bert , Ríos María , Rössner Gertrud E. , Sánchez Israel M. , Schulz Georg , Wang Shiqi , Costeur Loïc 
Published: December 2022

AbstractExtrinsic and intrinsic factors impact diversity. On deep-time scales, the extrinsic impact of climate and geology are crucial, but poorly understood. Here, we use the inner ear morphology of ruminant artiodactyls to test for a deep-time correlation between a low adaptive anatomical structure and both extrinsic and intrinsic variables. We apply geometric morphometric analyses in a phylogenetic frame to X-ray computed tomographic data from 191 ruminant species. Contrasting results across ruminant clades show that neutral evolutionary processes over time may strongly influence the evolution of inner ear morphology. Extant, ecologically diversified clades increase their evolutionary rate with decreasing Cenozoic global temperatures. Evolutionary rate peaks with the colonization of new continents. Simultaneously, ecologically restricted clades show declining or unchanged rates. These results suggest that both climate and paleogeography produced heterogeneous environments, which likely facilitated Cervidae and Bovidae diversification and exemplifies the effect of extrinsic and intrinsic factors on evolution in ruminants.
Spin-defect qubits in two-dimensional transition metal dichalcogenides operating at telecom wavelengths
Authors: Lee Yeonghun , Hu Yaoqiao , Lang Xiuyao , Kim Dongwook , Li Kejun , Ping Yuan , Fu Kai-Mei C. , Cho Kyeongjae 
Published: December 2022

AbstractSolid state quantum defects are promising candidates for scalable quantum information systems which can be seamlessly integrated with the conventional semiconductor electronic devices within the 3D monolithically integrated hybrid classical-quantum devices. Diamond nitrogen-vacancy (NV) center defects are the representative examples, but the controlled positioning of an NV center within bulk diamond is an outstanding challenge. Furthermore, quantum defect properties may not be easily tuned for bulk crystalline quantum defects. In comparison, 2D semiconductors, such as transition metal dichalcogenides (TMDs), are promising solid platform to host a quantum defect with tunable properties and a possibility of position control. Here, we computationally discover a promising defect family for spin qubit realization in 2D TMDs. The defects consist of transition metal atoms substituted at chalcogen sites with desirable spin-triplet ground state, zero-field splitting in the tens of GHz, and strong zero-phonon coupling to optical transitions in the highly desirable telecom band.
Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
Authors: Kameda-Smith Michelle M. , Zhu Helen , Luo En-Ching , Suk Yujin , Xella Agata , Yee Brian , Chokshi Chirayu , Xing Sansi , Tan Frederick , Fox Raymond G. , Adile Ashley A. , Bakhshinyan David , Brown Kevin , Gwynne William D. , Subapanditha Minomi , Miletic Petar , Picard Daniel , Burns Ian , Moffat Jason , Paruch Kamil , Fleming Adam , Hope Kristin , Provias John P. , Remke Marc , Lu Yu , Reya Tannishtha , Venugopal Chitra , Reimand Jüri , Wechsler-Reya Robert J. , Yeo Gene W. , Singh Sheila K. 
Published: December 2022

AbstractPediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.
A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes
Authors: Alharthi Jawaher , Bayoumi Ali , Thabet Khaled , Pan Ziyan , Gloss Brian S. , Latchoumanin Olivier , Lundberg Mischa , Twine Natalie A. , McLeod Duncan , Alenizi Shafi , Adams Leon A. , Weltman Martin , Berg Thomas , Liddle Christopher , George Jacob , Eslam Mohammed 
Published: December 2022

AbstractThe breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
Authors: Dall’Agnese Alessandra , Platt Jesse M. , Zheng Ming M. , Friesen Max , Dall’Agnese Giuseppe , Blaise Alyssa M. , Spinelli Jessica B. , Henninger Jonathan E. , Tevonian Erin N. , Hannett Nancy M. , Lazaris Charalampos , Drescher Hannah K. , Bartsch Lea M. , Kilgore Henry R. , Jaenisch Rudolf , Griffith Linda G. , Cisse Ibrahim I. , Jeppesen Jacob F. , Lee Tong I. , Young Richard A. 
Published: December 2022

AbstractInsulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.