bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of skin- and intestine microbial communities in migrating high Arctic lake whitefish and cisco
Authors: Hamilton Erin F. , Juurakko Collin L. , Engel Katja , Groot Peter van C. de , Casselman John M. , Greer Charles W. , Neufeld Josh D. , Walker Virginia K. 
Published: March 2023

AbstractAt high latitudes, lake whitefish (Coregonus clupeaformis) and others in the closely relatedCoregonusspecies complex (CSC), including cisco (C. autumnalisandC. sardinella), can be diadromous, seasonally transitioning between freshwater lakes and the Arctic Ocean. CSC skin- and intestine microbiomes were collected, facilitated by Inuit fishers at sites on and around King William Island, Nunavut, at the northern range limits of lake whitefish. Community composition was explored using 16S rRNA gene sequencing, with significant differences in microbiota dispersions depending on fishing site salinity for lake whitefish intestine and skin, as well as cisco skin. Overall, lake whitefish intestine communities appeared more variable than cisco and had higher Shannon diversity, suggesting that lake whitefish and their microbiomes could be more susceptible to environmental stress possibly leading to dysbiosis. Although cisco condition was similar among distinct seasonal habitats, the higher average lake whitefish condition in freshwater rivers suggests that fishing these diadromous whitefish in estuaries may be optimal from a sustainable fishery perspective. Taken together, the impact of changing habitats on fish condition and different microbial composition may inform new approaches to CSC health in fisheries and aquaculture, in addition to being relevant for northern Indigenous peoples with subsistence and economic interests in these resources.
The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity
Authors: Brunet Manon , Vargas Claire , Fanjul Marjorie , Pieruccioni Laetitia , Varry Damien , Labrousse Guillaume , Lulka Hubert , Capilla Florence , Couvelard Anne , Gigoux Véronique , Guillermet-Guibert Julie , Torrisani Jérôme , Dufresne Marlène 
Published: March 2023

AbstractBackground & AimsAlthough specialized and dedicated to the production of digestive enzymes, pancreatic acinar cells harbor a high plasticity and are able to modify their identity. They undergo reversible acinar-to-ductal cell metaplasia (ADM) through epigenetic silencing of the acinar lineage gene program mainly controlled by PTF1a (Pancreas Transcription Factor 1a). ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. We investigated the role of the E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12), involved in PTF1a degradation, in pancreatic carcinogenesis.MethodsWe used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant Trp53 (R172H). We performed RNA sequencing analysis from acinar cells and cell lines derived from mice models tumors. We investigated the impact of TRIP12 deficiency on acute pancreatitis, tumor formation and metastasis development.ResultsTRIP12 is overexpressed in human pancreatic preneoplastic lesions and tumors. We show that a conditional deletion of TRIP12 in the pancreas during murine embryogenesis alters pancreas homeostasis and acinar cell genes expression patterns in adults. EGF induced-ADM is suppressed in TRIP12-depleted pancreatic acini. In vivo, a loss of TRIP12 prevents acini to develop ADM in response to pancreatic injury, the formation of Kras-induced pancreatic preneoplastic lesions, and impairs tumors and metastasis formation in the presence of mutated Trp53. TRIP12 is required for Claudin18.2 isoform expression in pancreatic tumors cells.ConclusionsOur study identifies TRIP12 as a novel regulator of acinar fate in the adult pancreas with an important dual role in pancreatic carcinogenesis, in initiation steps and in metastatic behavior of tumor cells.SynopsisThis study shows that Thyroid hormone Receptor Interacting Protein 12 plays an important dual role in the initiation steps and invasion of pancreatic carcinogenesis. Moreover, expression of TRIP12 switches on the expression of Claudin-18, a targetable biomarker of pancreatic tumors.
KRAB zinc finger proteins ZNF587/ZNF417 protect lymphoma cells from replicative stress-induced inflammation
Authors: Martins Filipe , Rosspopoff Olga , Carlevaro-Fita Joana , Forey Romain , Offner Sandra , Planet Evarist , Pulver Cyril , Pak HuiSong , Huber Florian , Michaux Justine , Bassani-Sternberg Michal , Turelli Priscilla , Trono Didier 
Published: March 2023

ABSTRACTHeterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress can lead to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) are epigenetic modulators, which for many control heterochromatin at transposable element (TE)-embedded regulatory sequences. We identified a cluster of 18 KZFPs associated with poor prognosis in diffuse large B cell lymphoma (DLBCL). We found their upregulation to correlate with increased copy number alterations and suppression of immune responses in tumor samples. Upon depleting two that target evolutionarily recent TEs, the primate-specific ZNF587 and ZNF417 paralogs, the proliferation of DLBCL cell lines was drastically impaired and replicative stress abruptly induced with marked alterations of the chromatin landscape and multiplication of DNA replication origins. Furthermore,ZNF587/417knockdown upregulated interferon/inflammatory-related genes through activation of the cGAS-STING DNA sensing pathway, augmented the susceptibility of tumor cells to macrophage-mediated phagocytosis, and modified their immunogenicity through an increased surface expression of HLA-I and reshuffling of their immunopeptidome. ZNF587 and ZNF417 are thus pro-oncogenic factors allowing for higher degrees of genetic instability through attenuation of replicative stress and secondary inflammation, an influence that likely facilitates the clonal expansion, diversification, and immune evasion of cancer cells.
A Poisson distribution-based general model of cancer rates and a cancer risk-dependent theory of aging
Authors: Yu Wenbo , Gargett Tessa 
Published: March 2023

AbstractThis article presents a formula for modeling the lifetime incidence of cancer in humans. The formula utilizes a Poisson distribution-based “np” model to predict cancer incidence, with “n” representing the effective number of cell turnover and “p” representing the probability of single-cell transformation. The model accurately predicts the observed incidence of cancer in humans when cell turnover reduction is taken into account. The model also suggests that cancer development is ultimately inevitable. The article proposes a theory of aging based on this concept, called the “np” theory (Nuts Poisoned). According to this theory, an organism maintains its order by balancing cellular entropy through continuous proliferation. However, cellular information entropy increases irreversibly over time, restricting the total number of cells an organism can generate throughout its lifetime. When cell division slows down and fails to compensate for the entropy increase of the system, aging occurs. Essentially, aging is the phenomenon of running out of predetermined cell resources. Different species have evolved separate strategies to utilize their limited cell resources throughout their life cycle.
Conserved cysteine residues in Kaposi’s sarcoma herpesvirus ORF34 are necessary for viral production and viral pre-initiation complex formation
Authors: Watanabe Tadashi , McGraw Aidan , Narayan Kedhar , Tibebe Hasset , Kuriyama Kazushi , Nishimura Mayu , Izumi Taisuke , Fujimuro Masahiro , Ohno Shinji 
Published: March 2023

ABSTRACTKaposi’s sarcoma herpesvirus (KSHV) ORF34 plays a significant role as a component of the viral pre-initiation complex (vPIC), which is indispensable for late gene expression across beta and gamma herpesviruses. Although the key role of ORF34 within the vPIC and its function as a hub protein have been recognized, further clarification regarding its specific contribution to vPIC functionality and interactions with other components is required. This study employed a deep-learning algorithm-assisted structural model of ORF34, revealing highly conserved amino acid residues across human beta- and gamma-herpesviruses localized in structured domains. Thus, we engineered ORF34 alanine-scanning mutants by substituting conserved residues with alanine. These mutants were evaluated for their ability to interact with other vPIC factors and restore viral production in cells harboring the ORF34-deficient KSHV-BAC. Our experimental results highlight the crucial role of the 4 cysteine residues conserved in ORF34: a tetrahedral arrangement consisting of a pair of C-Xn-C consensus motifs. This suggests the potential incorporation of metal cations in interacting with ORF24 and ORF66 vPIC components, facilitating late gene transcription, and promoting overall virus production by capturing metal cations. In summary, our findings underline the essential role of conserved cysteines in KSHV ORF34 for effective vPIC assembly and viral replication, thereby enhancing our understanding of the complex interplay between the vPIC components.IMPORTANCEThe initiation of late gene transcription is universally conserved across the gamma- and beta-herpesvirus families. This process employs a viral pre-initiation complex (vPIC), which is analogous to a cellular PIC. Although KSHV ORF34 is a critical factor for viral replication and is a component of the vPIC, the specifics of vPIC formation and the essential domains crucial for its function remain unclear. Structural predictions suggest that the 4 conserved cysteines (C170, C175, C256, and C259) form a tetrahedron that coordinates the metal cation. We further investigated the role of these conserved amino acids in interactions with other vPIC components, late gene expression, and virus production, to demonstrate for the first time that these cysteines are pivotal for these functions. This discovery not only deepens our comprehensive understanding of ORF34 and vPIC dynamics but also lays the groundwork for more detailed studies on herpesvirus replication mechanisms in future research.
Mutations inembB406 are associated with low-level ethambutol resistance in CanadianMycobacterium tuberculosisisolates
Authors: Hiebert Morgan R. , Sharma Meenu K. , Rabb Melissa J. , Karlowsky Lisa J. , Bergman Kiana S. , Soualhine Hafid 
Published: March 2023

AbstractBackgroundInMycobacterium tuberculosis, molecular predictions of ethambutol resistance rely primarily on the detection of mutations withinembB. However, discordance betweenembB406 mutations and phenotypic drug sensitivity questions its clinical significance. This study aims to decipher the association ofembB406 mutations with ethambutol resistance inM. tuberculosis.MethodsAllM. tuberculosisisolates from our culture collection containingembB406 mutations (n=16) and pan-sensitive control isolates (n=10) were selected for this study. Phenotypic drug susceptibility testing for ethambutol was performed in duplicate on the BACTEC™ MGIT™ 960 at concentrations of 2, 3, 4, and 5 μg/mL with strain H37Rv as assay control. Whole genome sequencing was performed on Illumina Miseq for drug resistance predictions (MyKrobe Predictor v.0.7.0), phylogenomics (SNVPhyl v.1.2.3) and single nucleotide polymorphism analysis (Snippy).ResultsTwoembB406 mutation subtypes were found among 16 strains: Gly406Asp and Gly406Ala. MyKrobe predicted all strains of either subtype to be ethambutol resistant. However, 12 of 16 strains appear phenotypically sensitive at 5 μg/mL but exhibit variable resistance between 2-4 μg/mL. Of these 12 strains, a newly described frameshift mutation in regulatorembR(Gln258fs) was found in 9 strains.ConclusionsMutations inembB406 are associated with low-level ethambutol resistance currently undetectable by the critical concentration of 5 μg/mL for ethambutol. Novel mutations are predicted to exacerbate variability in ethambutol resistance. We suggest amendment to molecular and phenotypic drug susceptibility testing to improve ethambutol DST sensitivity and specificity as well as concordance between rapid and gold standard methods.
Molecular pathology of acute respiratory distress syndrome, mechanical ventilation and abnormal coagulation in severe COVID-19
Authors: Soulé Antoine , Ma William , Liu Katelyn Yixiu , Allard Catherine , Qureshi Salman , Tremblay Karine , Emad Amin , Rousseau Simon 
Published: March 2023

AbstractSystemic inflammation in critically ill patients can lead to serious consequences such as acute respiratory distress syndrome (ARDS), a condition characterized by the presence of lung inflammation, edema, and impaired gas exchange, associated with poor survival. Understanding molecular pathobiology is essential to improve critical care of these patients. To this end, we use multimodal profiles of SARS-CoV-2 infected hospitalized participants to the Biobanque Québécoise de la COVID-19 (BQC-19) to characterize endophenotypes associated with different degrees of disease severity. Proteomic, metabolomic, and genomic characterization supported a role for neutrophil-associated procoagulant activity in severe COVID-19 ARDS that is inversely correlated with sphinghosine-1 phosphate plasma levels. Fibroblast Growth Factor Receptor (FGFR) and SH2-containing transforming protein 4 (SHC4) signaling were identified as molecular features associated with endophenotype 6 (EP6). Mechanical ventilation in EP6 was associated with alterations in lipoprotein metabolism. These findings help define the molecular mechanisms related to specific severe outcomes, that can be used to identify early unfavorable clinical trajectories and treatable traits to improve the survival of critically ill patients.
Prevalence of anemia, associated risk factors and outcome in CHUK, Rwanda: a prospective observational study
Authors: Havugimana Phocas , Ndahimana Raphael , Babane Felix , Umutesi Ernestine , Ntihinyurwa Polyphile , Mushimiyimana Diane , Masaisa Florence , Ntabanganyimana Etienne 
Published: March 2023

ABSTRACTBackgroundAdmitted patients with anemia are at increased morbidity and mortality risk as well as length of hospital stay. It affects more than 2 billion people worldwide and is causing significant morbidity and mortality. Its etiology is varying with many predisposing factors including nutritional deficiencies, infections, Malignancies, chronic inflammations and other chronic diseases like autoimmune diseases, chronic liver disease, and chronic kidney disease.MethodsWe performed a non-randomized, prospective observational study of 143 patients admitted in Internal Medicine between March and April 2021, we assessed their hemoglobin level in order to determine the prevalence of anemia. The demographic and clinical data were collected using a designed questionnaire. All patients found to have anemia were followed for outcome assessment (either discharge or died).ResultsThe prevalence of anemia was high (52.4%) among 143 admitted patients in Internal Medicine, CHUK. Patients with HIV, cancer and chronic kidney disease had 5.84-, 4.11- and 3.79-times risk of having anemia respectively. In 75 patients who had anemia 10 patients died among them 5 patients were having severe anemia; 25 patients were 60 years old and above; 60 patients had normocytic anemia and they had an average of length of hospital stay of 20.6 days, patients with severe anemia, length of hospital stay was 28 days.ConclusionThis study demonstrated a high prevalence of anemia which is associated with high mortality rate among admitted patients in CHUK. Priority should be given to the preventive medicine, optimal management of chronic disease and geriatric medicine.
Spatio-temporal distributions of COVID-19 vaccine doses uptake in the Netherlands: A Bayesian ecological modelling analysis
Authors: Wang Haoyi , Varol Tugce , Gültzow Thomas , Zimmermann Hanne M. L. , Ruiter Robert A.C. , Jonas Kai J. 
Published: March 2023

AbstractBackgroundIn the transitioning era towards the COVID-19 endemic, there is still a sizable population that has never been vaccinated against COVID-19 in the Netherlands. To identify regions and populations that have a lower chance of vaccination uptake, this study provides a spatio-temporal estimation of the relative chance of COVID-19 vaccination uptake for the first, second, and the booster doses in the Netherlands on both municipality level and the public health services (regional) level.MethodsData on COVID-19 vaccination uptake were retrieved from the publicly available national COVID-19 surveillance dataset. We used a Bayesian spatio-temporal modelling technique with the integrated nested Laplace approximation to account for the spatial structure and the space-time interaction. Additionally, we used an ecological regression modelling technique which takes into account areal level socio-demographic characteristics to adjust for their potential impact on the chance of the regional vaccination uptake.ResultsOur findings revealed a heterogenous spatio-temporal distribution of the relative chance of COVID-19 vaccination uptake with highly overlapping trends of all three vaccination doses. Internal heterogeneity of COVID-19 vaccination uptake within one public health services region on the municipality level was also identified. The Dutch main urban area and the most religiously conservative regions were identified to have a lower-than-average chance of COVID-19 vaccination uptake compared to the rest of the country. Ecological regression modelling analysis revealed that regions with a higher proportion of non-Western immigrants had a lower chance of COVID-19 vaccination uptake for all vaccination scenarios.ConclusionThe obtained estimates should inform national and local COVID-19 vaccination policies and service strategies in the Netherlands for the ongoing COVID-19 campaign on the second booster. Namely, more regional efforts and services may be needed to close ‘vaccination gaps’ and optimise COVID-19 health-related outcomes, especially with regard to regions with a relatively higher proportion of marginalised populations.
Integrated metabolic and genetic analysis reveals distinct features of primary differentiated thyroid cancer and its metastatic potential in humans
Authors: Cararo-Lopes Eduardo , Sawant Akshada , Moore Dirk , Ke Hua , Shi Fuqian , Laddha Saurabh , Chen Ying , Sharma Anchal , Naumann Jake , Guo Jessie Yanxiang , Gomez Maria , Ibrahim Maria , Smith Tracey L , Riedlinger Gregory M. , Lattime Edmund C. , Trooskin Stanley , Ganesan Shridar , Su Xiaoyang , Pasqualini Renata , Arap Wadih , De Subhajyoti , Chan Chang S. , White Eileen 
Published: March 2023

ABSTRACTDifferentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach.TRANSLATIONAL RELEVANCEIn this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.Graphical Abstract
Estimation of the number of RSV-associated hospitalisations in adults in the European Union
Authors: Osei-Yeboah Richard , Spreeuwenberg Peter , Riccio Marco Del , Fischer Thea K. , Cavling Amanda , Boas Håkon , van Boven Michiel , Wang Xin , Lehtonen Toni , Bangert Mathieu , Campbell Harry , Paget John 
Published: March 2023

AbstractBackgroundRespiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in older adults that can result in hospitalisations and death. Estimating RSV- associated hospitalisation is critical for planning RSV-related healthcare needs for the ageing population across Europe.MethodsWe gathered national RSV-associated hospitalisation estimates from the REspiratory Syncytial virus Consortium in EUrope (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006 to 2017. We extrapolated these estimates to 28 EU countries using nearest-neighbour matching, multiple imputations, and two sets of 10 indicators.ResultsOn average, 158 229 (95%CI: 140 865-175 592) RSV-associated hospitalisations occur annually among adults in the EU (above 18 years); 92% of these hospitalisations occur in adults over 65 years. Among 75-84 years old, the annual average is estimated at 74 519 (95%CI: 69 923-79 115) at a rate of 2.24 (95%CI: 2.10-2.38) per 1000 adults. Among adults aged ≥85 years, the annual average is estimated at 37 904 (95%CI: 32 444-43 363) at a rate of 2.99 (95%CI: 2.56-3.42).ConclusionOur estimates of RSV-associated hospitalisations in older adults are the first analysis integrating available data to provide estimates of the disease burden in this population across the EU. Importantly, for a condition which was considered in the past to be primarily a disease of young children, the average annual hospitalisation estimate in adults was lower but of a similar magnitude to the estimate in young children aged 0-4 years: 158 229 (95%CI: 140 865–175 592) versus 245 244 (95%CI: 224 688 –265 799).