bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia
Authors: Ganesan Rajkumar , Chennupati Vijaykumar , Ramachandran Balaji , Hansen Michael Riis , Singh Sanjaya , Grewal Iqbal S. 
Published: February 2021

AbstractDespite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3+ T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2+ γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9+ γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9+ γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9+ γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.
Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants
Authors: Saarentaus Elmo Christian , Havulinna Aki Samuli , Mars Nina , Ahola-Olli Ari , Kiiskinen Tuomo Tapio Johannes , Partanen Juulia , Ruotsalainen Sanni , Kurki Mitja , Urpa Lea Martta , Chen Lei , Perola Markus , Salomaa Veikko , Veijola Juha , Männikkö Minna , Hall Ira M. , Pietiläinen Olli , Kaprio Jaakko , Ripatti Samuli , Daly Mark , Palotie Aarno 
Published: February 2021

AbstractCopy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.
Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies
Authors: Geraldo Luiz Henrique Medeiros , Spohr Tânia Cristina Leite de Sampaio , Amaral Rackele Ferreira do , Fonseca Anna Carolina Carvalho da , Garcia Celina , Mendes Fabio de Almeida , Freitas Catarina , dosSantos Marcos Fabio , Lima Flavia Regina Souza 
Published: February 2021

AbstractLysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.
Aberrantly high activation of a FoxM1–STMN1 axis contributes to progression and tumorigenesis in FoxM1-driven cancers
Authors: Liu Jun , Li Jipeng , Wang Ke , Liu Haiming , Sun Jianyong , Zhao Xinhui , Yu Yanping , Qiao Yihuan , Wu Ye , Zhang Xiaofang , Zhang Rui , Yang Angang 
Published: February 2021

AbstractFork-head box protein M1 (FoxM1) is a transcriptional factor which plays critical roles in cancer development and progression. However, the general regulatory mechanism of FoxM1 is still limited. STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules. It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients. But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear. In this study, we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer. Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay, plate clone formation assay, soft agar assay in vitro and xenograft mouse model in vivo. Our results showed that FoxM1 promotes cell proliferation by upregulating STMN1. Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level. Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors. Moreover, a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis. Our findings suggest that a general FoxM1-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma, gastric cancer and colorectal cancer. The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.
Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia
Authors: Mojarad Bahareh A. , Yin Yue , Manshaei Roozbeh , Backstrom Ian , Costain Gregory , Heung Tracy , Merico Daniele , Marshall Christian R. , Bassett Anne S. , Yuen Ryan K. C. 
Published: February 2021

AbstractThe range of genetic variation with potential clinical implications in schizophrenia, beyond rare copy number variants (CNVs), remains uncertain. We therefore analyzed genome sequencing data for 259 unrelated adults with schizophrenia from a well-characterized community-based cohort previously examined with chromosomal microarray for CNVs (none with 22q11.2 deletions). We analyzed these genomes for rare high-impact variants considered causal for neurodevelopmental disorders, including single-nucleotide variants (SNVs) and small insertions/deletions (indels), for potential clinical relevance based on findings for neurodevelopmental disorders. Also, we investigated a novel variant type, tandem repeat expansions (TREs), in 45 loci known to be associated with monogenic neurological diseases. We found several of these variants in this schizophrenia population suggesting that these variants have a wider clinical spectrum than previously thought. In addition to known pathogenic CNVs, we identified 11 (4.3%) individuals with clinically relevant SNVs/indels in genes converging on schizophrenia-relevant pathways. Clinical yield was significantly enriched in females and in those with broadly defined learning/intellectual disabilities. Genome analyses also identified variants with potential clinical implications, including TREs (one inDMPK; two inATXN8OS) and ultra-rare loss-of-function SNVs inZMYM2(a novel candidate gene for schizophrenia). Of the 233 individuals with no pathogenic CNVs, we identified rare high-impact variants (i.e., clinically relevant or with potential clinical implications) for 14 individuals (6.0%); some had multiple rare high-impact variants. Mean schizophrenia polygenic risk score was similar between individuals with and without clinically relevant rare genetic variation; common variants were not sufficient for clinical application. These findings broaden the individual and global picture of clinically relevant genetic risk in schizophrenia, and suggest the potential translational value of genome sequencing as a single genetic technology for schizophrenia.
Targeted multi-epitope switching enables straightforward positive/negative selection of CAR T cells
Authors: Mosti Laura , Langner Lukas M. , Chmielewski Kay O. , Arbuthnot Patrick , Alzubi Jamal , Cathomen Toni 
Published: February 2021

AbstractChimeric antigen receptor (CAR) T cell technology has enabled successfully novel concepts to treat cancer patients, with substantial remission rates in lymphoid malignancies. This cell therapy is based on autologous T lymphocytes that are genetically modified to express a CAR that recognizes tumor-associated antigens and mediates the elimination of the respective tumor cells. Current limitations include laborious manufacturing procedures as well as severe immunological side effects upon administration of CAR T cells. To address these limitations, we integrated RQR8, a multi-epitope molecule harboring a CD34 epitope and two CD20 mimotopes, alongside a CD19-targeting CAR, into the CD52 locus. Using CRISPR-Cas9 and adeno-associated virus-based donor vectors, some 60% of genome-edited T cells were CAR+/CD20+/CD34+/CD52− without further selection. This could be increased to >95% purity after CD34 tag-based positive selection. These epitope-switched CAR T cells retained cell killing competence against CD19+ tumor cells, and were resistant to alemtuzumab (anti-CD52) but sensitive to rituximab (anti-CD20) in complement-dependent cytotoxicity assays. In conclusion, gene editing-based multiple epitope switching represents a promising development with the potential to improve both the manufacturing procedure as well as the clinical safety of CAR T cells.
Insights into triterpene synthesis and unsaturated fatty-acid accumulation provided by chromosomal-level genome analysis of Akebia trifoliata subsp. australis
Authors: Huang Hui , Liang Juan , Tan Qi , Ou Linfeng , Li Xiaolin , Zhong Caihong , Huang Huilin , Møller Ian Max , Wu Xianjin , Song Songquan 
Published: February 2021

AbstractAkebia trifoliata subsp. australis is a well-known medicinal and potential woody oil plant in China. The limited genetic information available for A. trifoliata subsp. australis has hindered its exploitation. Here, a high-quality chromosome-level genome sequence of A. trifoliata subsp. australis is reported. The de novo genome assembly of 682.14 Mb was generated with a scaffold N50 of 43.11 Mb. The genome includes 25,598 protein-coding genes, and 71.18% (485.55 Mb) of the assembled sequences were identified as repetitive sequences. An ongoing massive burst of long terminal repeat (LTR) insertions, which occurred ~1.0 million years ago, has contributed a large proportion of LTRs in the genome of A. trifoliata subsp. australis. Phylogenetic analysis shows that A. trifoliata subsp. australis is closely related to Aquilegia coerulea and forms a clade with Papaver somniferum and Nelumbo nucifera, which supports the well-established hypothesis of a close relationship between basal eudicot species. The expansion of UDP-glucoronosyl and UDP-glucosyl transferase gene families and β-amyrin synthase-like genes and the exclusive contraction of terpene synthase gene families may be responsible for the abundant oleanane-type triterpenoids in A. trifoliata subsp. australis. Furthermore, the acyl-ACP desaturase gene family, including 12 stearoyl-acyl-carrier protein desaturase (SAD) genes, has expanded exclusively. A combined transcriptome and fatty-acid analysis of seeds at five developmental stages revealed that homologs of SADs, acyl-lipid desaturase omega fatty acid desaturases (FADs), and oleosins were highly expressed, consistent with the rapid increase in the content of fatty acids, especially unsaturated fatty acids. The genomic sequences of A. trifoliata subsp. australis will be a valuable resource for comparative genomic analyses and molecular breeding.
R2R3-MYB transcription factors, StmiR858 and sucrose mediate potato flavonol biosynthesis
Authors: Lin Sen , Singh Rajesh K. , Moehninsi  , Navarre Duroy A. 
Published: February 2021

AbstractFlavonols and other phenylpropanoids protect plants from biotic and abiotic stress and are dietarily desirable because of their health-promoting properties. The ability to develop new potatoes (Solanum tuberosum) with optimal types and amounts of phenylpropanoids is limited by lack of knowledge about the regulatory mechanisms. Exogenous sucrose increased flavonols, whereas overexpression of the MYB StAN1 induced sucrolytic gene expression. Heterologous StAN1 protein bound promoter fragments from sucrolytic genes (SUSY1andINV1). Two additional MYBs and one microRNA were identified that regulated potato flavonols. Overexpression analysis showedMYB12AandCincreased amounts of flavonols and other phenylpropanoids. Endogenous flavonol amounts in light-exposed organs were much higher those in the dark. Expression levels ofStMYB12AandCwere high in flowers but low in tubers. Transient overexpression of miR858 altered potato flavonol metabolism. Endogenous StmiR858 expression was much lower in flowers than leaves and correlated with flavonol amounts in these organs. Collectively, these findings support the hypothesis that sucrose, MYBs, and miRNA control potato phenylpropanoid metabolism in a finely tuned manner that includes a feedback loop between sucrose and StAN1. These findings will aid in the development of potatoes with phenylpropanoid profiles optimized for crop performance and human health.
KSN heterozygosity is associated with continuous flowering of Rosa rugosa Purple branch
Authors: Bai Mengjuan , Liu Jinyi , Fan Chunguo , Chen Yeqing , Chen Hui , Lu Jun , Sun Jingjing , Ning Guogui , Wang Changquan 
Published: February 2021

AbstractRose (Rosaspp.) plants flower via two contrasting methods: once flowering (OF) and continuous flowering (CF). Purple branch is a rare continuously flowering variety ofRosa rugosathat is extensively cultivated in China. However, the genetic basis of its CF behavior is unknown. We demonstrated that Purple branch is heterozygous for theTFL1homologKSN. OneKSNallele with a 9 kb Copia insertion was found to be identical to that from continuously floweringRosa chinensisOld blush. The other allele was found to be a functional wild-type allele. The overall expression ofKSNwas closely linked to the floral transition, and it was significantly repressed in continuously flowering Purple branch compared with OF Plena. The promoter region of the normalKSNallele was hypermethylated, and histone methylation at H3H4, H3K9, and H3K27 of theKSNgene locus was modified in continuously flowering Purple branch. Silencing of the DNA methyltransferase genesMET1andCMT3and the histone methyltransferase geneSUVR5in Purple branch led to enhancedKSNexpression, but silencing of the histone demethylase geneJMJ12suppressedKSNexpression. Therefore, the CF habit of Purple branch may be due to reduced expression ofKSNcaused by the halved dose and may be associated with epigenetic modifications together with retrotransposon insertions along the chromosome. Our study revealed a novel mechanism underlying the CF behavior of rose plants.
Protein S-nitrosation differentially modulates tomato responses to infection by hemi-biotrophic oomycetes of Phytophthora spp.
Authors: Jedelská Tereza , Sedlářová Michaela , Lochman Jan , Činčalová Lucie , Luhová Lenka , Petřivalský Marek 
Published: February 2021

AbstractRegulation of protein function by reversible S-nitrosation, a post-translational modification based on the attachment of nitroso group to cysteine thiols, has emerged among key mechanisms of NO signalling in plant development and stress responses. S-nitrosoglutathione is regarded as the most abundant low-molecular-weight S-nitrosothiol in plants, where its intracellular concentrations are modulated by S-nitrosoglutathione reductase. We analysed modulations of S-nitrosothiols and protein S-nitrosation mediated by S-nitrosoglutathione reductase in cultivated Solanum lycopersicum (susceptible) and wild Solanum habrochaites (resistant genotype) up to 96 h post inoculation (hpi) by two hemibiotrophic oomycetes, Phytophthora infestans and Phytophthora parasitica. S-nitrosoglutathione reductase activity and protein level were decreased by P. infestans and P. parasitica infection in both genotypes, whereas protein S-nitrosothiols were increased by P. infestans infection, particularly at 72 hpi related to pathogen biotrophy–necrotrophy transition. Increased levels of S-nitrosothiols localised in both proximal and distal parts to the infection site, which suggests together with their localisation to vascular bundles a signalling role in systemic responses. S-nitrosation targets in plants infected with P. infestans identified by a proteomic analysis include namely antioxidant and defence proteins, together with important proteins of metabolic, regulatory and structural functions. Ascorbate peroxidase S-nitrosation was observed in both genotypes in parallel to increased enzyme activity and protein level during P. infestans pathogenesis, namely in the susceptible genotype. These results show important regulatory functions of protein S-nitrosation in concerting molecular mechanisms of plant resistance to hemibiotrophic pathogens.
A glucose meter interface for point-of-care gene circuit-based diagnostics
Authors: Amalfitano Evan , Karlikow Margot , Norouzi Masoud , Jaenes Katariina , Cicek Seray , Masum Fahim , Sadat Mousavi Peivand , Guo Yuxiu , Tang Laura , Sydor Andrew , Ma Duo , Pearson Joel D. , Trcka Daniel , Pinette Mathieu , Ambagala Aruna , Babiuk Shawn , Pickering Bradley , Wrana Jeff , Bremner Rod , Mazzulli Tony , Sinton David , Brumell John H. , Green Alexander A. , Pardee Keith 
Published: February 2021

AbstractRecent advances in cell-free synthetic biology have given rise to gene circuit-based sensors with the potential to provide decentralized and low-cost molecular diagnostics. However, it remains a challenge to deliver this sensing capacity into the hands of users in a practical manner. Here, we leverage the glucose meter, one of the most widely available point-of-care sensing devices, to serve as a universal reader for these decentralized diagnostics. We describe a molecular translator that can convert the activation of conventional gene circuit-based sensors into a glucose output that can be read by off-the-shelf glucose meters. We show the development of new glucogenic reporter systems, multiplexed reporter outputs and detection of nucleic acid targets down to the low attomolar range. Using this glucose-meter interface, we demonstrate the detection of a small-molecule analyte; sample-to-result diagnostics for typhoid, paratyphoid A/B; and show the potential for pandemic response with nucleic acid sensors for SARS-CoV-2.
PopDel identifies medium-size deletions simultaneously in tens of thousands of genomes
Authors: Niehus Sebastian , Jónsson Hákon , Schönberger Janina , Björnsson Eythór , Beyter Doruk , Eggertsson Hannes P. , Sulem Patrick , Stefánsson Kári , Halldórsson Bjarni V. , Kehr Birte 
Published: February 2021

AbstractThousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel’s running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.
Calculation and interpretation of classical turning surfaces in solids
Authors: Kaplan Aaron D. , Clark Stewart J. , Burke Kieron , Perdew John P. 
Published: February 2021

AbstractClassical turning surfaces of Kohn–Sham potentials separate classically allowed regions (CARs) from classically forbidden regions (CFRs). They are useful for understanding many chemical properties of molecules but need not exist in solids, where the density never decays to zero. At equilibrium geometries, we find that CFRs are absent in perfect metals, rare in covalent semiconductors at equilibrium, but common in ionic and molecular crystals. In all materials, CFRs appear or grow as the internuclear distances are uniformly expanded. They can also appear at a monovacancy in a metal. Calculations with several approximate density functionals and codes confirm these behaviors. A classical picture of conduction suggests that CARs should be connected in metals, and disconnected in wide-gap insulators, and is confirmed in the limits of extreme compression and expansion. Surprisingly, many semiconductors have no CFR at equilibrium, a key finding for density functional construction. Nonetheless, a strong correlation with insulating behavior can still be inferred. Moreover, equilibrium bond lengths for all cases can be estimated from the bond type and the sum of the classical turning radii of the free atoms or ions.