bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does weight loss reduce the incidence of total knee and hip replacement for osteoarthritis?—A prospective cohort study among middle-aged and older adults with overweight or obesity
Authors: Jin Xingzhong , Gibson Alice A. , Gale Joanne , Schneuer Francisco , Ding Ding , March Lyn , Sainsbury Amanda , Nassar Natasha 
Published: May 2021

Abstract
Objective
This study aims to investigate the association between weight change and total knee or hip replacement (TKR or THR) for OA among middle-aged and older adults with overweight or obesity.

Method
Weight data were collected in 2006–2009 and in 2010 from the 45 and Up Study—a population-based cohort aged ≥45 years in New South Wales, Australia. Participants were included if they had a baseline body mass index (BMI) ≥ 25 kg/m2 and no history of TKR or THR. Weight change was categorised into four groups: >7.5% loss; >5–7.5% loss; stable (≤5% change) and >5% gain. Hospital admission data were linked to identify TKR and THR for OA, and multivariable Cox regression was used to assess risk of TKR and THR.

Results
Of 23,916 participants, 2139 lost >7.5% weight, 1655 lost 5–7.5% weight, and 4430 gained >5% weight. Over 5.2 years, 1009 (4.2%) underwent TKR and 483 (2.0%) THR. Compared to weight-stable, weight loss of >7.5% was associated with reduced risk of TKR after adjusting for age, sex, BMI, socioeconomic and lifestyle factors (hazard ratio 0.69, 95%CI 0.54–0.87), but had no association with THR. Weight loss of 5–7.5% was not associated with altered risk of either TKR or THR. Weight gain was associated with increased risk of THR after adjusting for confounders, but not TKR.

Conclusion
This study suggests that a weight loss target >7.5% is required to reduce the risk of TKR in adults with overweight or obesity. Weight gain should be avoided as it increases the risk of THR.
Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells
Authors: Wobus Manja , Mies Anna , Asokan Nandini , Oelschlägel Uta , Möbus Kristin , Winter Susann , Cross Michael , Weidner Heike , Rauner Martina , Hofbauer Lorenz C. , Bornhäuser Martin , Platzbecker Uwe 
Published: May 2021

AbstractThe bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder
Authors: Sharma Akhil , Harutyunyan Arman , Schneider Bernard L. , Moszczynska Anna 
Published: May 2021

AbstractThere is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.
Assessing olfactory, memory, social and circadian phenotypes associated with schizophrenia in a genetic model based on Rim
Authors: Hidalgo Sergio , Campusano Jorge M. , Hodge James J. L. 
Published: May 2021

AbstractSchizophrenia shows high heritability and several of the genes associated with this disorder are involved in calcium (Ca2+) signalling and synaptic function. One of these is theRab-3 interacting molecule-1(RIM1), which has recently been associated with schizophrenia by Genome Wide Association Studies (GWAS). However, its contribution to the pathophysiology of this disorder remains unexplored. In this work, we useDrosophilamutants of the orthologue ofRIM1,Rim, to model some aspects of the classical and non-classical symptoms of schizophrenia.Rimmutants showed several behavioural features relevant to schizophrenia including social distancing and altered olfactory processing. These defects were accompanied by reduced evoked Ca2+influx and structural changes in the presynaptic terminals sent by the primary olfactory neurons to higher processing centres. In contrast, expression ofRim-RNAiin the mushroom bodies (MBs), the main memory centre in flies, spared learning and memory suggesting a differential role of Rim in different synapses. Circadian deficits have been reported in schizophrenia. We observed circadian locomotor activity deficits inRimmutants, revealing a role of Rim in the pacemaker ventral lateral clock neurons (LNvs). These changes were accompanied by impaired day/night remodelling of dorsal terminal synapses from a subpopulation of LNvs and impaired day/night release of the circadian neuropeptide pigment dispersing factor (PDF) from these terminals. Lastly, treatment with the commonly used antipsychotic haloperidol rescuedRimlocomotor deficits to wildtype. This work characterises the role of Rim in synaptic functions underlying behaviours disrupted in schizophrenia.
Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies
Authors: Rögnvaldsson Sæmundur , Love Thorvardur Jon , Thorsteinsdottir Sigrun , Reed Elín Ruth , Óskarsson Jón Þórir , Pétursdóttir Íris , Sigurðardóttir Guðrún Ásta , Viðarsson Brynjar , Önundarson Páll Torfi , Agnarsson Bjarni A. , Sigurðardóttir Margrét , Þorsteinsdóttir Ingunn , Ólafsson Ísleifur , Þórðardóttir Ásdís Rósa , Eyþórsson Elías , Jónsson Ásbjörn , Björnsson Andri S. , Gunnarsson Gunnar Þór , Pálsson Runólfur , Indriðason Ólafur Skúli , Gíslason Gauti Kjartan , Ólafsson Andri , Hákonardóttir Guðlaug Katrín , Brinkhuis Manje , Halldórsdóttir Sara Lovísa , Ásgeirsdóttir Tinna Laufey , Steingrímsdóttir Hlíf , Danielsen Ragnar , Dröfn Wessman Inga , Kampanis Petros , Hultcrantz Malin , Durie Brian G. M. , Harding Stephen , Landgren Ola , Kristinsson Sigurður Yngvi 
Published: May 2021

AbstractMonoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis
Authors: Maiti Guru P. , Sinha Sutapa , Mahmud Hasan , Boysen Justin , Mendez Mariana T. , Vesely Sara K. , Holter-Chakrabarty Jennifer , Kay Neil E. , Ghosh Asish K. 
Published: May 2021

AbstractMitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O2−) levels with increased accumulation of hydrogen peroxide (H2O2) in CLL cells vs. normal B-cells. Further analysis indicated that mitochondrial superoxide dismutase (SOD)2, which converts O2− into H2O2 remained deacetylated in CLL cells due to SIRT3 overexpression resulting its constitutive activation. In addition, catalase expression was also reduced in CLL cells suggesting impairment of H2O2-conversion into water and O2 which may cause H2O2-accumulation. Importantly, we identified two CpG-islands in the catalase promoter and discovered that while the distal CpG-island (−3619 to −3765) remained methylated in both normal B-cells and CLL cells, variable degrees of methylation were discernible in the proximal CpG-island (−174 to −332) only in CLL cells. Finally, treatment of CLL cells with a demethylating agent increased catalase mRNA levels. Functionally, ROS accumulation in CLL cells activated the AXL survival axis while upregulated SIRT3, suggesting that CLL cells rapidly remove highly reactive O2− to avoid its cytotoxic effect but maintain increased H2O2-level to promote cell survival. Therefore, abrogation of aberrantly activated cell survival pathways using antioxidants can be an effective intervention in CLL therapy in combination with conventional agents.
Long intergenic non-coding RNA 00473 promotes proliferation and migration of gastric cancer via the miR-16-5p/CCND2 axis and by regulating AQP3
Authors: Zhuo Shuaishuai , Sun Miaomiao , Bai Rumeng , Lu Die , Di Shihao , Ma Tianshi , Zou Zigui , Li Hongxia , Zhang Zhihong 
Published: May 2021

AbstractGastric cancer (GC) is one of the most common malignancies worldwide, but its molecular mechanisms remain unclear. Increasing evidence indicates that long non-coding RNAs (LncRNAs) play a pivotal role in various cancers recently. Our present study focused on exploring the function of long intergenic non-coding RNA 00473 (LINC00473) in GC. In this study, we found that LINC00473 expression was aberrantly increased in tumor tissues compared with the paired para-cancerous tissues. The expression of high LINC00473 in GC was notably correlated with a higher risk of lymphatic metastasis, a higher incidence of vascular cancer embolus, and advanced TNM stage. Further experiments showed that the overexpression of LINC00473 could promote the proliferation and metastasis of GC cells both in vitro and in vivo. The apoptosis of GC cells increased significantly by the decrease of LINC00473. Mechanistically, LINC00473 could sponge miR-16-5p in the cytoplasm and relieve its suppression of CCND2. Moreover, AQP3 was found to be a significant downstream target gene for LINC00473 through RNA transcriptome sequencing, as demonstrated by qRT-PCR and western blot. Overexpression of LINC00473 can partially reverse the effects of AQP3 decrease on GC proliferation and metastasis. LINC00473 regulated AQP3 expression through CREB was confirmed by western blot. Our research indicates that LINC00473/miR-16-5p/CCND2 axis plays a role in the proliferation of GC and modulates AQP3 to influence GC cell metastasis, making it a potential therapeutic target for GC.
Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice
Authors: Teufel Stefan , Köckemann Petra , Fabritius Christine , Wolff Lena I. , Bertrand Jessica , Pap Thomas , Hartmann Christine 
Published: May 2021

AbstractAgonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.
N6-methyladenosine (m6A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer
Authors: Tang Jun , Han Tianci , Tong Wei , Zhao Jian , Wang Wei 
Published: May 2021

AbstractN6-methyladenosine (m6A) modification has been convincingly identified to be a critical regulator in human cancer. However, the contribution of m6A to NSCLC gefitinib resistance is still largely unknown. Here, we screened and identified that m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. Functionally, KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro. Depletion of KIAA1429 repressed the tumor growth of PC9-GR cells in vivo. Mechanistically, KIAA1429 enhanced the mRNA stability of HOXA1 through targeting its 3′-untranslated regions (3′-UTR). Overall, our findings indicate that KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which may provide a feasible therapeutic target for NSCLC.
Importance of circadian timing for aging and longevity
Authors: Acosta-Rodríguez Victoria A. , Rijo-Ferreira Filipa , Green Carla B. , Takahashi Joseph S. 
Published: May 2021

AbstractDietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.
Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage
Authors: Dass Sheena , Shunmugam Serena , Berry Laurence , Arnold Christophe-Sebastien , Katris Nicholas J. , Duley Samuel , Pierrel Fabien , Cesbron-Delauw Marie-France , Yamaryo-Botté Yoshiki , Botté Cyrille Y. 
Published: May 2021

AbstractApicomplexa are obligate intracellular parasites responsible for major human diseases. Their intracellular survival relies on intense lipid synthesis, which fuels membrane biogenesis. Parasite lipids are generated as an essential combination of fatty acids scavenged from the host and de novo synthesized within the parasite apicoplast. The molecular and metabolic mechanisms allowing regulation and channeling of these fatty acid fluxes for intracellular parasite survival are currently unknown. Here, we identify an essential phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as the central metabolic nexus responsible for controlled lipid synthesis sustaining parasite development. Lipidomics reveal that TgLIPIN controls the synthesis of diacylglycerol and levels of phosphatidic acid that regulates the fine balance of lipids between storage and membrane biogenesis. Using fluxomic approaches, we uncover the first parasite host-scavenged lipidome and show that TgLIPIN prevents parasite death by ‘lipotoxicity’ through effective channeling of host-scavenged fatty acids to storage triacylglycerols and membrane phospholipids.
Observation of topological superconductivity in a stoichiometric transition metal dichalcogenide 2M-WS2
Authors: Li Y. W. , Zheng H. J. , Fang Y. Q. , Zhang D. Q. , Chen Y. J. , Chen C. , Liang A. J. , Shi W. J. , Pei D. , Xu L. X. , Liu S. , Pan J. , Lu D. H. , Hashimoto M. , Barinov A. , Jung S. W. , Cacho C. , Wang M. X. , He Y. , Fu L. , Zhang H. J. , Huang F. Q. , Yang L. X. , Liu Z. K. , Chen Y. L. 
Published: May 2021

AbstractTopological superconductors (TSCs) are unconventional superconductors with bulk superconducting gap and in-gap Majorana states on the boundary that may be used as topological qubits for quantum computation. Despite their importance in both fundamental research and applications, natural TSCs are very rare. Here, combining state of the art synchrotron and laser-based angle-resolved photoemission spectroscopy, we investigated a stoichiometric transition metal dichalcogenide (TMD), 2M-WS2 with a superconducting transition temperature of 8.8 K (the highest among all TMDs in the natural form up to date) and observed distinctive topological surface states (TSSs). Furthermore, in the superconducting state, we found that the TSSs acquired a nodeless superconducting gap with similar magnitude as that of the bulk states. These discoveries not only evidence 2M-WS2 as an intrinsic TSC without the need of sensitive composition tuning or sophisticated heterostructures fabrication, but also provide an ideal platform for device applications thanks to its van der Waals layered structure.
Supervised dimensionality reduction for big data
Authors: Vogelstein Joshua T. , Bridgeford Eric W. , Tang Minh , Zheng Da , Douville Christopher , Burns Randal , Maggioni Mauro 
Published: May 2021

AbstractTo solve key biomedical problems, experimentalists now routinely measure millions or billions of features (dimensions) per sample, with the hope that data science techniques will be able to build accurate data-driven inferences. Because sample sizes are typically orders of magnitude smaller than the dimensionality of these data, valid inferences require finding a low-dimensional representation that preserves the discriminating information (e.g., whether the individual suffers from a particular disease). There is a lack of interpretable supervised dimensionality reduction methods that scale to millions of dimensions with strong statistical theoretical guarantees. We introduce an approach to extending principal components analysis by incorporating class-conditional moment estimates into the low-dimensional projection. The simplest version, Linear Optimal Low-rank projection, incorporates the class-conditional means. We prove, and substantiate with both synthetic and real data benchmarks, that Linear Optimal Low-Rank Projection and its generalizations lead to improved data representations for subsequent classification, while maintaining computational efficiency and scalability. Using multiple brain imaging datasets consisting of more than 150 million features, and several genomics datasets with more than 500,000 features, Linear Optimal Low-Rank Projection outperforms other scalable linear dimensionality reduction techniques in terms of accuracy, while only requiring a few minutes on a standard desktop computer.
Transcriptome-wide association analysis of brain structures yields insights into pleiotropy with complex neuropsychiatric traits
Authors: Zhao Bingxin , Shan Yue , Yang Yue , Yu Zhaolong , Li Tengfei , Wang Xifeng , Luo Tianyou , Zhu Ziliang , Sullivan Patrick , Zhao Hongyu , Li Yun , Zhu Hongtu 
Published: May 2021

AbstractStructural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10−8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10−31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.