bluuebunny/crossref_metadata_2025_split huggingface dataset:
The value of single-molecule real-time technology in the diagnosis of rare thalassemia variants and analysis of phenotype–genotype correlation
Authors: Luo Shiqiang , Chen Xingyuan , Zeng Dingyuan , Tang Ning , Yuan Dejian , Zhong Qingyan , Mao Aiping , Xu Ruofan , Yan Tizhen 
Published: October 2021

AbstractTo compare single-molecule real-time technology (SMRT) and conventional genetic diagnostic technology of rare types of thalassemia mutations, and to analyze the molecular characteristics and phenotypes of rare thalassemia gene variants, we used 434 cases with positive hematology screening as the cohort, then used SMRT technology and conventional gene diagnosis technology [(Gap-PCR, multiple ligation probe amplification technology (MLPA), PCR-reverse dot blot (RDB)] for thalassemia gene screening. Among the 434 enrolled cases, conventional technology identified 318 patients with variants (73.27%) and 116 patients without variants (26.73%), SMRT identified 361 patients with variants (83.18%), and 73 patients without variants (16.82%). The positive detection rate of SMRT was 9.91% higher than conventional technology. Combination of the two methods identified 485 positive alleles among 49 types of variant. The genotypes of 354 cases were concordant between the two methods, while 80 cases were discordant. Among the 80 cases, 76 cases had variants only identified in SMRT method, 3 cases had variants only identified in conventional method, and 1 false positive result by the traditional PCR detection technology. Except the three variants in HS40 and HBG1-HBG2 loci, which was beyond the design of SMRT method in this study, all the other discordant variants identified by SMRT were validated by further Sanger sequencing or MLPA. The hematological phenotypic parameters of 80 discordant cases were also analyzed. SMRT technology increased the positive detection rate of thalassemia genes, and detected rare thalassemia cases with variable phenotypes, which had great significance for clinical thalassemia gene screening.
Lnc-PFAR facilitates autophagy and exacerbates pancreatic fibrosis by reducing pre-miR-141 maturation in chronic pancreatitis
Authors: Zhang Tao , Zhang Guangquan , Yang Wenbo , Chen Hongze , Hu Jisheng , Zhao Zhongjie , Cheng Chundong , Li Guanqun , Xie Yu , Li Yilong , Kong Rui , Wang Yongwei , Wang Gang , Chen Hua , Bai Xue-Wei , Pan Shangha , Sun Bei , Li Le 
Published: October 2021

AbstractChronic pancreatitis (CP) is described as progressive inflammatory fibrosis of pancreas, accompanied with irreversible impaired endocrine and exocrine insufficiency. Pancreatic stellate cells (PSCs) are widely distributed in the stroma of the pancreas and PSCs activation has been shown as one of the leading causes for pancreatic fibrosis. Our previous study has revealed that autophagy is dramatically activated in CP tissues, which facilitates PSCs activation and pancreatic fibrosis. Long non-coding RNAs (LncRNAs) have been recognized as crucial regulators for fibrosis-related diseases. LncRNAs interact with RNA binding protein or construct competitive endogenous RNA (ceRNA) hypothesis which elicited the fibrotic processes. Until now, the effects of lncRNAs on PSCs activation and pancreatic fibrosis have not been clearly explored. In this study, a novel lncRNA named Lnc-PFAR was found highly expressed in mouse and human CP tissues. Our data revealed that Lnc-PFAR facilitates PSCs activation and pancreatic fibrosis via RB1CC1-induced autophagy. Lnc-PFAR reduces miR-141 expression by suppressing pre-miR-141 maturation, which eventually upregulates the RB1CC1 and fibrosis-related indicators expression. Meanwhile, Lnc-PFAR enhanced PSCs activation and pancreatic fibrosis through trigging autophagy. Our study interrogates a novel lncRNA-induced mechanism in promoting the development of pancreatic fibrosis, and Lnc-PFAR is suggested to be a prospective therapeutic target in clinical scenarios.
MINDY1 promotes breast cancer cell proliferation by stabilizing estrogen receptor α
Authors: Tang Jianing , Luo Yongwen , Long Guo , Zhou Ledu 
Published: October 2021

AbstractBreast cancer is the most commonly diagnosed malignant tumor among females. Estrogen receptor α (ERα) is initially expressed in 70% of breast cancers and is a well-known target of endocrine therapy for ERα-positive breast cancer. In the present study, we identified MINDY1, a member belongs to the motif interacting with Ubcontaining novel DUB family (MINDY), as a potential deubiquitylase of ERα in breast cancer. There was a positive correlation between ERα and MINDY1 protein levels in human breast cancer tissues. We found that high expression of MINDY1 was associated with poor prognosis. MINDY1 interacted with ERα, thereby mediating the deubiquitination of ERα and increased its stability in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased the ERα protein level and ERα signaling activity in breast cancer cells. Specifically, MINDY1 associated with the N-terminal of ERα via its catalytic domain, thus inhibiting K48-specific poly-ubiquitination process on ERα protein. In addition, MINDY1 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells. Finally, overexpression of ERα could rescue the MINDY1 depletion-induced growth inhibition both in vitro and in vivo, suggesting that MINDY1 promotes breast carcinogenesis through increasing ERα stability. Overall, our study proposed a novel post-translational mechanism of ERα in supporting breast cancer progression. Targeting the MINDY1 may prove to be a promising strategy for patients with ERα-positive breast cancer.
ZBTB38 suppresses prostate cancer cell proliferation and migration via directly promoting DKK1 expression
Authors: Ding Guanxiong , Lu Wei , Zhang Qing , Li Kai , Zhou Huihui , Wang Fei , Zhao Chunchun , Fan Caibin , Wang Jianqing 
Published: October 2021

AbstractProstate cancer is still one of the most common malignancies in men all around the world. The mechanism of how prostate cancer initiates and develops is still not clear. Here in this study, we show that tumor suppressorZBTB38could suppress the migration and proliferation of prostate cancer cells. We find lowerZBTB38expression in prostate cancer tissues, which also strongly predicts a poorer prognosis of prostate cancer.ZBTB38bindsDKK1(DickkopfWNTsignaling pathway inhibitor 1) locus and promotesDKK1expression in prostate cancer cell lines. Consistently, reduction ofDKK1expression significantly restoresZBTB38-mediated suppression of migration and proliferation of prostate cancer cell lines. Mechanistically, we find thatZBTB38primarily binds the promoters of target genes, and differentially regulates the expression of 1818 genes. We also identifyPRKDC(protein kinase, DNA-activated, catalytic subunit) as aZBTB38-interacting protein that could repress the function ofZBTB38in suppressing migration and proliferation of prostate cancer cells. Taken together, our results indicate thatZBTB38could repress cell migration and proliferation in prostate cancer via promotingDKK1expression, and also provide evidence supportingZBTB38as a potential prognosis marker for prostate cancer.
Impact of intracellular innate immune receptors on immunometabolism
Authors: Chou Wei-Chun , Rampanelli Elena , Li Xin , Ting Jenny P.-Y. 
Published: October 2021

AbstractImmunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.
Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals
Authors: van der Schoot Vyne , Haer-Wigman Lonneke , Feenstra Ilse , Tammer Femke , Oerlemans Anke J. M. , van Koolwijk Martine P. A. , van Agt Frans , Arens Yvonne H. J. M. , Brunner Han G. , Vissers Lisenka E. L. M. , Yntema Helger G. 
Published: October 2021

AbstractUnsolicited findings (UFs) are uncovered unintentionally and predispose to a disease unrelated to the clinical question. The frequency and nature of UFs uncovered in clinical practice remain largely unexplored. We here evaluated UFs identified during a 5-year period in which 16,482 index patients received clinical whole-exome sequencing (WES). UFs were identified in 0.58% (95/16,482) of index patients, indicating that the overall frequency of UFs in clinical WES is low. Fewer UFs were identified using restricted disease-gene panels (0.03%) than when using whole-exome/Mendeliome analysis (1.03%). The UF was disclosed to 86 of 95 individuals, for reasons of medical actionability. Only 61% of these UFs reside in a gene that is listed on the “ACMG59”-list, representing a list of 59 genes for which the American College of Medical Genetics recommends UF disclosure. The remaining 39% were grouped into four categories: disorders similar to “ACMG59”-listed disorders (25%); disorders for which disease manifestation could be influenced (7%); UFs providing reproductive options (2%); and UFs with pharmacogenetic implications (5%). Hence, our experience shows that UFs predisposing to medically actionable disorders affect a broader range of genes than listed on the “ACMG59”, advocating that a pre-defined gene list is too restrictive, and that UFs may require ad hoc evaluation of medical actionability. While both the identification and disclosure of UFs depend on local policy, our lessons learned provide general essential insight into the nature and odds of UFs in clinical exome sequencing.
Elimination of oxygen sensitivity in α-titanium by substitutional alloying with Al
Authors: Chong Yan , Zhang Ruopeng , Hooshmand Mohammad S. , Zhao Shiteng , Chrzan Daryl C. , Asta Mark , Morris J. W. , Minor Andrew M. 
Published: October 2021

AbstractIndividually, increasing the concentration of either oxygen or aluminum has a deleterious effect on the ductility of titanium alloys. For example, extremely small amounts of interstitial oxygen can severely deteriorate the tensile ductility of titanium, particularly at cryogenic temperatures. Likewise, substitutional aluminum will decrease the ductility of titanium at low-oxygen concentrations. Here, we demonstrate that, counter-intuitively, significant additions of both Al and O substantially improves both strength and ductility, with a 6-fold increase in ductility for a Ti-6Al-0.3 O alloy as compared to a Ti-0.3 O alloy. The Al and O solutes act together to increase and sustain a high strain-hardening rate by modifying the planar slip that predominates into a delocalized, three-dimensional dislocation pattern. The mechanism can be attributed to decreasing stacking fault energy by Al, modification of the “shuffle” mechanism of oxygen-dislocation interaction by the repulsive Al-O interaction in Ti, and micro-segregation of Al and O by the same cause.
Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo
Authors: Jann Johann-Christoph , Mossner Maximilian , Riabov Vladimir , Altrock Eva , Schmitt Nanni , Flach Johanna , Xu Qingyu , Nowak Verena , Obländer Julia , Palme Iris , Weimer Nadine , Streuer Alexander , Jawhar Ahmed , Darwich Ali , Jawhar Mohammad , Metzgeroth Georgia , Nolte Florian , Hofmann Wolf-Karsten , Nowak Daniel 
Published: October 2021

AbstractThe bone marrow (BM) stroma in myeloid neoplasms is altered and it is hypothesized that this cell compartment may also harbor clonal somatically acquired mutations. By exome sequencing of in vitro expanded mesenchymal stromal cells (MSCs) from n = 98 patients with myelodysplastic syndrome (MDS) and n = 28 healthy controls we show that these cells accumulate recurrent mutations in genes such as ZFX (n = 8/98), RANK (n = 5/98), and others. MDS derived MSCs display higher mutational burdens, increased replicative stress, senescence, inflammatory gene expression, and distinct mutational signatures as compared to healthy MSCs. However, validation experiments in serial culture passages, chronological BM aspirations and backtracking of high confidence mutations by re-sequencing primary sorted MDS MSCs indicate that the discovered mutations are secondary to in vitro expansion but not present in primary BM. Thus, we here report that there is no evidence for clonal mutations in the BM stroma of MDS patients.
Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave
Authors: Davis Jessica T. , Chinazzi Matteo , Perra Nicola , Mu Kunpeng , Pastore y Piontti Ana , Ajelli Marco , Dean Natalie E. , Gioannini Corrado , Litvinova Maria , Merler Stefano , Rossi Luca , Sun Kaiyuan , Xiong Xinyue , Longini Ira M. , Halloran M. Elizabeth , Viboud Cécile , Vespignani Alessandro 
Published: October 2021

AbstractConsiderable uncertainty surrounds the timeline of introductions and onsets of local transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) globally1–7. Although a limited number of SARS-CoV-2 introductions were reported in January and February 2020 (refs.8,9), the narrowness of the initial testing criteria, combined with a slow growth in testing capacity and porous travel screening10, left many countries vulnerable to unmitigated, cryptic transmission. Here we use a global metapopulation epidemic model to provide a mechanistic understanding of the early dispersal of infections and the temporal windows of the introduction of SARS-CoV-2 and onset of local transmission in Europe and the USA. We find that community transmission of SARS-CoV-2 was likely to have been present in several areas of Europe and the USA by January 2020, and estimate that by early March, only 1 to 4 in 100 SARS-CoV-2 infections were detected by surveillance systems. The modelling results highlight international travel as the key driver of the introduction of SARS-CoV-2, with possible introductions and transmission events as early as December 2019 to January 2020. We find a heterogeneous geographic distribution of cumulative infection attack rates by 4 July 2020, ranging from 0.78% to 15.2% across US states and 0.19% to 13.2% in European countries. Our approach complements phylogenetic analyses and other surveillance approaches and provides insights that can be used to design innovative, model-driven surveillance systems that guide enhanced testing and response strategies.
HIV-2 Vpx neutralizes host restriction factor SAMHD1 to promote viral pathogenesis
Authors: Mohamed Ahlam , Bakir Talal , Al-Hawel Huda , Al-Sharif Ibtihaj , Bakheet Razan , Kouser Lubna , Murugaiah Valarmathy , Al-Mozaini Maha 
Published: October 2021

AbstractSAMHD1, a human host factor found in myeloid cells which restricts HIV-1 replication. It depletes the dNTPs pool for viral cDNA syntheses, thus preventing the viral replication in the cells. The viral accessory protein, Vpx, exists only in SIVmac/HIV-2 particles. Vpx in SIVmac can induce proteosomal degradation of SAMHD1, which then leads to a decrease in the cytoplasmic dNTP pool. The protein–protein interaction between Vpx and SAMHD1 and its consequences are still unclear. Methods: In this study, we cloned, for the first time, Vpx gene from a HIV-2 infected patient and found up to 30% sequence variation compared to known HIV-2 strains. We then analyzed the role of SAMHD1 protein expression in transfected THP-1 and U937 cells by transfecting with the Vpx gene derived from SIVmac, HIV-2 from the NIH sample as well as HIV-2 from a Saudi patient. We found that Vpx gene expression led to reduced levels of intracellular SAMHD1. When the supernatants of the transfected cell lines were examined for secreted cytokines, chemokines and growth factors, Vpx expression seemed to be suppressive of pro-inflammatory response, and skewed the immune response towards an anti-inflammatory response. These results suggest that Vpx can act at two levels: clearance of intracellular restriction factor and suppression of cytokine storm: both aimed at long-term latency and host–pathogen stand-off, suggesting that Vpx is likely to be a potential therapeutic target.
Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS
Authors: Goon Danial Efendy , Ab-Rahim Sharaniza , Mohd Sakri Amir Hakimi , Mazlan Musalmah , Tan Jen Kit , Abdul Aziz Mardiana , Mohd Noor Norizal , Ibrahim Effendi , Sheikh Abdul Kadir Siti Hamimah 
Published: October 2021

AbstractExcessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.
Optimal virtual water flows for improved food security in water-scarce countries
Authors: Maroufpoor Saman , Bozorg-Haddad Omid , Maroufpoor Eisa , Gerbens-Leenes P. Winnie , Loáiciga Hugo A. , Savic Dragan , Singh Vijay P. 
Published: October 2021

AbstractThe worsening water scarcity has imposed a significant stress on food production in many parts of the world. This stress becomes more critical when countries seek self-sufficiency. A literature review shows that food self-sufficiency has not been assessed as the main factor in determining the optimal cultivation patterns. However, food self-sufficiency is one of the main policies of these countries and requires the most attention and concentration. Previous works have focused on the virtual water trade to meet regional food demand and to calculate trade flows. The potential of the trade network can be exploited to improve the cropping pattern to ensure food and water security. To this end, and based on the research gaps mentioned, this study develops a method to link intra-country trade networks, food security, and total water footprints (WFs) to improve food security. The method is applied in Iran, a water-scarce country. The study shows that 781 × 106 m3 of water could be saved by creating a trade network. Results of the balanced trade network are input to a multi-objective optimization model to improve cropping patterns based on the objectives of achieving food security and preventing water crises. The method provides 400 management scenarios to improve cropping patterns considering 51 main crops in Iran. Results show a range of improvements in food security (19–45%) and a decrease in WFs (2–3%). The selected scenario for Iran would reduce the blue water footprint by 1207 × 106 m3, and reduce the cropland area by 19 × 103 ha. This methodology allows decision makers to develop policies that achieve food security under limited water resources in arid and semi-arid regions.
Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature
Authors: Brydges Christopher R. , Fiehn Oliver , Mayberg Helen S. , Schreiber Henry , Dehkordi Siamak Mahmoudian , Bhattacharyya Sudeepa , Cha Jungho , Choi Ki Sueng , Craighead W. Edward , Krishnan Ranga R. , Rush A. John , Dunlop Boadie W. , Kaddurah-Daouk Rima ,   the Mood Disorders Precision Medicine Consortium, Penninx Brenda , Binder Elizabeth , Kastenmüller Gabi , Arnold Matthias , Nevado-Helgado Alejo , Blach Colette , Milaneschi Yuri , Knauer-Arloth Janine , Jansen Rich , Mook-Kanamori Dennis , Han Xianlin , Baillie Rebecca , Rinaldo Piero 
Published: October 2021

AbstractIt is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite’s effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 “Predictors of Antidepressant Treatment Response: The Emory CIDAR” https://clinicaltrials.gov/ct2/show/NCT00360399.