bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of the DNA Fork Remodeling Protein Smarcal1 Impairs the Replication Stress Response in Proliferating Hematopoietic Cells
Authors: Kushinsky Saul , Puccetti Matthew V , Adams Clare M , Eischen Christine M 
Published: February 2021

Rapidly proliferating hematopoietic cells are particularly prone to threats to genomic integrity through replication stress. The response to replication stress involves complex molecular machinery to prevent replication fork collapse, avoid accumulation of DNA damage, and ensure the completion of DNA synthesis. Smarcal1, a DNA remodeling enzyme, has been linked to the replication stress response through stabilization, repair, and restart of stalled DNA replication forks. In humans, complete loss of function of Smarcal1 leads to the pleiotropic disorder Schimke immuno-osseous dysplasia (SIOD), which is characterized, in part, by a severe lymphoid immunodeficiency that leaves patients susceptible to opportunistic infections. Currently, the mechanisms driving the clinical immunodeficient phenotype of SIOD and the in vivo functions of Smarcal1 in hematopoietic cells remain largely unexplored. We evaluated the contribution of Smarcal1 to normal and stressed/emergency hematopoiesis, using a Smarcal1 knockout mouse model and hematopoietic cell replication stresses such as low-dose radiation, 5-fluorouracil, bone marrow transplantation, and oncogene- driven proliferation. We determined that, while loss of Smarcal1 does not affect hematopoietic stem and progenitor cells (HSPCs) or mature hematopoietic cell populations at a normal "resting" state, Smarcal1 is required in these cells undergoing proliferative stress. Following DNA replication stress, we detected defects in multiple Smarcal1-deficient hematopoietic cell populations. We also observed that loss of Smarcal1 led to significantly increased levels of replication stress, DNA damage, and apoptosis in proliferating cells. Through bone marrow transplantation, we determined that the deficiencies observed were not due to a defect in the bone marrow environment or an inability of the HSPCs to home to the bone marrow. Thus, our results reveal that Smarcal1 is critical to maintaining hematopoietic cell survival and function under conditions of DNA replication stress. Our data also suggest that the immunodeficiency of patients with Smarcal1 mutations may be due to an inability of hematopoietic cells, especially HSPCs, to properly respond to replication stress and proliferate. Since wild-type bone marrow is able to fully reconstitute and function in a Smarcal1-deficient environment, bone marrow transplantation may be an effective therapy for immunodeficient SIOD patients.

Disclosures
Eischen: AbbVie Inc.: Research Funding.
Cellular Fibronectin Promotes Deep Vein Thrombosis in Obese Mice
Authors: Dhanesha Nirav , Jain Manish , Doddapattar Prakash , Undas Anetta , Chauhan Anil K 
Published: February 2021

Objective: Obesity is a significant risk factor for deep vein thrombosis (DVT). The mechanisms of increased DVT in preexisting comorbid condition of obesity remain poorly understood. Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), is known to contribute to thrombo-inflammation in the experimental models. However, the role of Fn-EDA in modulation of venous thrombosis in context of obesity is not elucidated yet.
Approach and Results: We found that cellular Fn-EDA levels were significantly elevated in plasma of venous thromboembolism (VTE) patients that positively correlated with body mass index (BMI). To investigate whether Fn-EDA promotes venous thrombosis in obese condition, WT and Fn-EDA-/- mice were either fed a control or high-fat diet (HF-diet) for 12-weeks. DVT was induced by inferior vena cava stenosis and evaluated after 48 hours. We found that HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF-fed Fn-EDA-/- mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF-fed WT mice that was concomitant with improved blood flow, reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDAfl/fl mice, which constitutively express Fn-EDA, reduced DVT compared with Fn-EDAfl/fl mice.
Conclusion: These results demonstrate a previously unknown role of Fn-EDA in the modulation of DVT, which may be an important mechanism promoting DVT in the setting of obesity.
Figure

Disclosures
No relevant conflicts of interest to declare.
Aberrant rRNA 2'-O-Methylation Causes Bone Marrow Failure and Defective Immune Function
Authors: Nachmani Daphna , Mendez Lourdes M. , Pandolfi Pier Paolo 
Published: February 2021

RNA modifications are emerging as key determinants of development and disease. Understanding the mechanisms regulating their functional impact is crucial to uncovering their relevance for disease pathology. The NPM1 gene is frequently a target of genetic alteration in hematological tumors, particularly of the myeloid lineage. While extensively studied, the mechanisms by which NPM1 exert its impact on HSPCs are still not fully elucidated. Recently, we have identified NPM1 as an essential regulator of rRNA 2'-O-methylation (2'OMe). We found that NPM1, through its RNA-binding activity, binds C/D box small nucleolar RNAs (snoRNAs) in the nucleolus, to regulate rRNA 2'OMe, and thereby controls translation. Additionally, we identified NPM1 germ-line mutations in dyskeratosis congenita patients presenting with BMF. Characterization of these mutations found them as selectively deficient in snoRNA binding, and thus their expression led to reduce 2'OMe levels and aberrant translation in patient cells. To causally link reduced 2'OMe to dyskeratosis congenita manifestation, we generated mice harboring a dyskeratosis congenita germ-line NPM1 mutation. The KI mice phenocopy both hematological and non-hematological DC features, thus casually linking mutated NPM1 and reduced 2'OMe to bone marrow failure. Currently, we are taking advantage of our Npm1-mutated mouse model to explore the role of 2'OMe in mature immune cell function. We find that aberrant 2'OMe in mature macrophages (due to Npm1 mutation) does not affect their maturation, however, it leads to altered functions. Specifically, we find that Npm1-mutated macrophages, with reduced 2'OMe, display reduced production of reactive oxygen species, chemotactic properties and phagocytic capacity. These studies demonstrate a role for Npm1 and 2'OMe in adult immune cells, and reveal the importance of translation regulation in both hematopoietic stem cells and mature macrophage function.
Figure

Disclosures
No relevant conflicts of interest to declare.
Modified Beac Conditioning Regimen with Idarubicin Followed By Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective for Invasive B-Cell Non-Hodgkin's Lymphoma Patients
Authors: Tian Chen 
Published: February 2021

High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC). We compared the outcomes of 72 B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn't occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group were a little longer than that of BEAC group. 2-year OS and PFS rate were higher in IEAC group compared to BEAC group. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase (LDH) level, remission of disease, modified regimen were related with the prognosis. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could effectively prolong the survival of patients.

Disclosures
No relevant conflicts of interest to declare.
Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism
Authors: Ten Cate Vincent , Prochaska Jürgen H. , Schulz Andreas , Koeck Thomas , Pallares Robles Alejandro , Lenz Michael , Eggebrecht Lisa , Rapp Steffen , Panova-Noeva Marina , Ghofrani H. Ardeschir , Meyer F. Joachim , Espinola-Klein Christine , Lackner Karl J. , Michal Matthias , Schuster Alexander K. , Strauch Konstantin , Zink Alexander M. , Laux Volker , Heitmeier Stefan , Konstantinides Stavros V. , Münzel Thomas , Andrade-Navarro Miguel A. , Leineweber Kirsten , Wild Philipp S. 
Published: February 2021

Abstract
Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
Redefining outcomes in immune TTP: an international working group consensus report
Authors: Cuker Adam , Cataland Spero R. , Coppo Paul , de la Rubia Javier , Friedman Kenneth D. , George James N. , Knoebl Paul N. , Kremer Hovinga Johanna A. , Lӓmmle Bernhard , Matsumoto Masanori , Pavenski Katerina , Peyvandi Flora , Sakai Kazuya , Sarode Ravi , Thomas Mari R. , Tomiyama Yoshiaki , Veyradier Agnès , Westwood John-Paul , Scully Marie 
Published: February 2021

Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti–von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.
Boolean implication analysis unveils candidate universal relationships in microbiome data
Authors: Vo Daniella , Singh Shayal Charisma , Safa Sara , Sahoo Debashis 
Published: February 2021

Abstract
Background
Microbiomes consist of bacteria, viruses, and other microorganisms, and are responsible for many different functions in both organisms and the environment. Past analyses of microbiomes focused on using correlation to determine linear relationships between microbes and diseases. Weak correlations due to nonlinearity between microbe pairs may cause researchers to overlook critical components of the data. With the abundance of available microbiome, we need a method that comprehensively studies microbiomes and how they are related to each other.

Results
We collected publicly available datasets from human, environment, and animal samples to determine both symmetric and asymmetric Boolean implication relationships between a pair of microbes. We then found relationships that are potentially invariants, meaning they will hold in any microbe community. In other words, if we determine there is a relationship between two microbes, we expect the relationship to hold in almost all contexts. We discovered that around 330,000 pairs of microbes universally exhibit the same relationship in almost all the datasets we studied, thus making them good candidates for invariants. Our results also confirm known biological properties and seem promising in terms of disease diagnosis.

Conclusions
Since the relationships are likely universal, we expect them to hold in clinical settings, as well as general populations. If these strong invariants are present in disease settings, it may provide insight into prognostic, predictive, or therapeutic properties of clinically relevant diseases. For example, our results indicate that there is a difference in the microbe distributions between patients who have or do not have IBD, eczema and psoriasis. These new analyses may improve disease diagnosis and drug development in terms of accuracy and efficiency.
Methodological approaches to imputing early-pregnancy weight based on weight measures collected during pregnancy
Authors: Yang Jiaxi , Wang Dongqing , Darling Anne Marie , Liu Enju , Perumal Nandita , Fawzi Wafaie W. , Wang Molin 
Published: February 2021

AbstractBackgroundEarly pregnancy weights are needed to quantify gestational weight gain accurately. Different methods have been used in previous studies to impute early-pregnancy weights. However, no studies have systematically compared imputed weight accuracy across different imputation techniques. This study aimed to compare four methodological approaches to imputing early-pregnancy weight, using repeated measures of pregnancy weights collected from two pregnancy cohorts in Tanzania.MethodsThe mean gestational ages at enrollment were 17.8 weeks for Study I and 10.0 weeks for Study II. Given the gestational age distributions at enrollment, early-pregnancy weights were extrapolated for Study I and interpolated for Study II. The four imputation approaches included: (i) simple imputation based on the nearest measure, (ii) simple arithmetic imputation based on the nearest two measures, (iii) mixed-effects models, and (iv) marginal models with generalized estimating equations. For the mixed-effects model and the marginal model with generalized estimating equation methods, imputation accuracy was further compared across varying degrees of model flexibility by fitting splines and polynomial terms. Additional analyses included dropping third-trimester weights, adding covariate to the models, and log-transforming weight before imputation. Mean absolute error was used to quantify imputation accuracy.ResultsStudy I included 1472 women with 6272 weight measures; Study II included 2131 individuals with 11,775 weight measures. Among the four imputation approaches, mixed-effects models had the highest accuracy (smallest mean absolute error: 1.99 kg and 1.60 kg for Studies I and II, respectively), while the other three approaches showed similar degrees of accuracy. Depending on the underlying data structure, allowing appropriate degree of model flexibility and dropping remote pregnancy weight measures may further improve the imputation performance.ConclusionsMixed-effects models had superior performance in imputing early-pregnancy weight compared to other commonly used strategies.
Age-related impairment of navigation and strategy in virtual star maze
Authors: Zhang Jia-Xin , Wang Lin , Hou Hai-Yan , Yue Chun-Lin , Wang Liang , Li Hui-Jie 
Published: February 2021

Abstract
Background
Although it is well known that aging impairs navigation performance, the underlying mechanisms remain largely unknown. Egocentric strategy requires navigators to remember a series of body-turns without relying on the relationship between environmental cues. Previous study suggested that the egocentric strategy, compared with non-egocentric strategy, was relatively unimpaired during aging. In this study, we aimed to examine strategy use during virtual navigation task and the underlying cognitive supporting mechanisms in older adults.

Methods
Thirty young adults and thirty-one older adults were recruited from the local community. This study adapted star maze paradigm using non-immersive virtual environment. Participants moved freely in a star maze with adequate landmarks, and were requested to find a fixed destination. After 9 learning trials, participants were probed in the same virtual star maze but with no salient landmarks. Participants were classified as egocentric or non-egocentric strategy group according to their response in the probe trial.

Results
The results revealed that older adults adopting egocentric strategy completed the navigation task as accurate as young adults, whereas older adults using non-egocentric strategy completed the navigation task with more detours and lower accuracy. The relatively well-maintained egocentric strategy in older adults was related to better visuo-spatial ability.

Conclusions
Visuo-spatial ability might play an important role in navigation accuracy and navigation strategy of older adults. This study demonstrated the potential value of the virtual star maze in evaluating navigation strategy and visuo-spatial ability in older adults.
Care homes, their communities, and resilience in the face of the COVID-19 pandemic: interim findings from a qualitative study
Authors: Marshall Fiona , Gordon Adam , Gladman John R. F. , Bishop Simon 
Published: February 2021

Abstract
Background
From late February 2020, English care homes rapidly adapted their practices in response to the COVID-19 pandemic. In addition to accommodating new guidelines and policies, staff had to adjust to rapid reconfiguration of services external to the home that they would normally depend upon for support. This study examined the complex interdependencies of support as staff responded to COVID-19. The aim was to inform more effective responses to the ongoing pandemic, and to improve understanding of how to work with care home staff and organisations after the pandemic has passed.

Methods
Ten managers of registered care homes in the East Midlands of England were interviewed by videoconference or phone about their experiences of the crisis from a structured organisational perspective. Analysis used an adapted organisational framework analysis approach with a focus on social ties and interdependencies between organisations and individuals.

Results
Three key groups of interdependencies were identified: care processes and practice; resources; and governance. Care home staff had to deliver care in innovative ways, making high stakes decisions in circumstances defined by: fluid ties to organisations outside the care home; multiple, sometimes conflicting, sources of expertise and information; and a sense of deprioritisation by authorities. Organisational responses to the pandemic by central government resulted in resource constraints and additional work, and sometimes impaired the ability of staff and managers to make decisions. Local communities, including businesses, third-sector organisations and individuals, were key in helping care homes overcome challenges. Care homes, rather than competing, were found to work together to provide mutual support. Resilience in the system was a consequence of dedicated and resourceful staff using existing local networks, or forging new ones, to overcome barriers to care.

Conclusions
This study identified how interdependency between care home organisations, the surrounding community, and key statutory and non-statutory organisations beyond their locality, shaped decision making and care delivery during the pandemic. Recognising these interdependencies, and the expertise shown by care home managers and staff as they navigate them, is key to providing effective healthcare in care homes as the pandemic progresses, and as the sector recovers afterwards.