Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation of oxidative stress in experimental periodontitis treated with myricetin

Aim: The aim of this study was to investigate the effects of systemically applied myricetin on oxidative stress and antioxidant status in experimental periodontitis of rats. Materials and Methods: 24 Wistar rats were used and randomly divided into three groups. Experimental periodontitis was induced by placing a silk ligature around first molars teeth of the rats for 15 days. Following removal of the ligatures, Group 1: saline; Group 2: myricetin and Group 3: doxycycline were administered systemically. Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD) enzyme and malondialdehyde (MDA) levels in serum; and SOD and MDA levels in gingival tissue were determined by biochemical analysis. Results: Serum TAS increased and serum TOS and OSI values decreased in myricetin and doxycycline treated groups compared to saline group (P0.016). Gingival tissue SOD activity was increased in the group treated with doxycycline compared with the group treated with saline (P
Information Chasing versus Adverse Selection

Contrary to the prediction of the classic adverse selection theory, more informed traders could receive better pricing relative to less informed traders in over-the-counter financial markets. Dealers actively chase informed orders to better position their future quotes and avoid winner's curse in subsequent trades. On a multi-dealer platform, dealers' incentive of information chasing exactly offsets their fear of adverse selection. In a more general setting, information chasing can dominate adverse selection when dealers face differentially informed speculators, while adverse selection dominates when dealers face differentially informed trades from a given speculator. These two seemingly contrasting predictions are supported by empirical evidence from the UK government bond market.
Hedge Accounting and Firms ’ Future Investment Spending

This study explores the effectiveness and consequences of hedge accounting rules under ASC 815 by investigating the relationship between derivative designation and future investments. Finance theory argues that hedging helps firms to overcome underinvestment problems, as it reduces the probability of liquidity shortfalls. We argue that this association holds only for derivatives designated for hedge accounting, which requires the fulfilment of strict effectiveness criteria. We find that only designated derivative assets are positively associated with future investments implying that the regulations under ASC 815 are generally implemented correctly and that the FASB has installed an effective signaling device about the success of firms’ hedging programs. However, firms using portfolio hedging strategies seemingly cannot designate some of their successful derivatives due to the often criticized restriction of hedge accounting to hedges at transaction-level. Our findings should interest researchers, practitioners and financial standard-setters, particularly in times when derivative use becomes increasingly important.
Role of police in preventing the spread of COVID-19 through social distancing, quarantine and lockdown: An evidence-based comparison of outcomes across two districts

The COVID-19 pandemic is a formidable challenge to societies and governments across the world. The non-medical interventions of social distancing, quarantine and lockdown have been adopted to prevent transmission of the disease by contact. In some countries, police have been used to enforce public health laws. This research analyses data from two districts in the State of Kerala, India to examine whether police efforts had any impact on the outcome of reducing transmission of the disease by contact. Analysing the different methods used by the police across the two districts, this study concludes that police efforts at non-medical interventions reduce the spread of the disease. The study also concludes that, in contrast to mere enforcement of public health laws and regulations, the strategic use of resources is an important factor in achieving better outcomes.
Mechanisms of circular RNA circ_0066147 on pancreatic cancer progression

Abstract Background The purpose of the study was to explore the precise parts of circ_0066147 (circular RNA [circRNA] scm-like with four mbt domains 1, circSFMBT1) in pancreatic cancer (PC) progression. Methods Ribonuclease R assay was used to confirm the stability of circ_0066147. circ_0066147, miR-326 and E2F transcription factor 2 (E2F2) expression levels was detected by quantitative reverse-transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration and invasion abilities were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, flow cytometry, wound-healing and transwell assays, respectively. Targeted relationships among circ_0066147, miR-326 and E2F2 were verified by the dual-luciferase reporter or RNA pull-down assay. Results circ_0066147 expression was upregulated in PC tissues and cells. circ_0066147 knockdown inhibited PC cell proliferation, migration, invasion and enhanced apoptosis in vitro, as well as weakened tumor growth in vivo. Mechanistically, circ_0066147 directly targeted miR-326 and circ_0066147 modulated E2F2 expression by miR-326. miR-326 mediated the regulation of circ_0066147 in PC cell behaviors in vitro. Furthermore, E2F2 was a functional target of miR-326 in modulating PC cell behaviors in vitro. Conclusion circ_0066147 regulated PC malignant progression in part depending on the miR-326/E2F2 axis, illuminating circ_0066147 was a potential prognostic marker and therapeutic target for PC management.
Functional dissection of human mitotic genes using CRISPR-Cas9 tiling screens

Kinetochores are large protein complexes that assemble at the centromere and bind to mitotic spindle microtubules to ensure accurate chromosome segregation. Like most protein-coding genes, the full multifunctional nature of kinetochore factors remains uncharacterized due to the limited experimental tools for unbiased dissection of human protein sequences. We developed a method that leverages CRISPR-Cas9 induced mutations to identify key functional regions within protein sequences required for cellular outgrowth. Our analysis of 48 human mitotic genes revealed hundreds of regions required for cell proliferation, including known domains and uncharacterized ones. We validated the essential nature for 15 of these regions, including amino acids 387-402 of Mad1, which identified an unknown domain that contributes to Mad1 kinetochore localization and chromosome segregation fidelity. Altogether, we demonstrate that CRISPR-Cas9-based tiling mutagenesis identifies key functional domains in protein-coding genes de novo, which elucidates separation of function mutants and allows functional annotation across the human proteome.
Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution

Background and objectives To understand how organisms evolve, it is fundamental to study how mutations emerge and establish. Here, we estimated the rate of mutation accumulation of SARS-CoV-2 in vitro and investigated the repeatability of its evolution when facing a new cell type but no immune or drug pressures. Methodology We performed experimental evolution with two strains of SARS-CoV-2, one carrying the originally described spike protein (CoV-2-D) and another carrying the D614G mutation that has spread worldwide (CoV-2-G). After 15 passages in Vero cells and whole genome sequencing, we characterized the spectrum and rate of the emerging mutations and looked for evidences of selection across the genomes of both strains. Results From the mutations accumulated, and excluding the genes with signals of selection, we estimate a spontaneous mutation rate of 1.25×10-6 nt-1 per infection cycle for both lineages of SARS-CoV-2. We further show that mutation accumulation is heterogeneous along the genome, with the spike gene accumulating mutations at rate five-fold higher than the genomic average. We also observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein. Conclusions and implications These results provide valuable information on how spontaneous mutations emerge in SARS-CoV-2 and on how selection can shape its genome towards adaptation to new environments. Lay summary Mutation is the ultimate source of variation. We estimated how the SARS-COV-2 virus—cause of the COVID-19 pandemic—mutates. Upon infecting cells, its genome can change at a rate of 0.04 per replication. We also find that this rate can change and that its spike protein can adapt, even within few replications.
Mechanisms of translation repression by the EIF4E1-4EIP cap-binding complex of Trypanosoma brucei: potential roles of the NOT complex and a terminal uridylyl transferase

Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3’-UTR, whether or not EIF4E1 is present. 4EIP is essential during the transition from the mammalian bloodstream form to the procyclic form that lives in the Tsetse vector. In contrast, EIF4E1 is dispensable during differentiation, but is required for establishment of growing procyclic forms. There are two competing models for EIF4E1 function: either EIF4E1 has translation initiation activity that is inhibited by 4EIP, or EIF4E1 acts only as an inhibitor. We here provide evidence for the second hypothesis. Even in the complete absence of 4EIP, EIF4E1 showed no detectable association with other translation initiation factors, and 4EIP loss caused no detectable change in 4E1-associated mRNAs. We found that 4EIP stabilises EIF4E1, probably through co-translational complex assembly, and that 4EIP directly recruits the cytosolic terminal uridylyl transferase TUT3 to EIF4E1/4EIP complexes. There was, however, no evidence that TUT3 is essential for 4EIP function; instead, some evidence implicated the NOT deadenylase complex.
c-di-AMP Is Essential for the Virulence of Enterococcus faecalis

Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis (cdaA) and degradation (dhhP and gdpP). ABSTRACT Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis (cdaA) and degradation (dhhP and gdpP). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (ΔcdaA strain) or c-di-AMP accumulation (ΔdhhP, ΔgdpP, and ΔdhhP ΔgdpP strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the ΔcdaA strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine ex vivo, and was virtually avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of the ΔcdaA strain also could be attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both in vitro and in vivo conditions. Collectively, these results demonstrate that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.
Transcriptomics of improved fruit retention by hexanal in ‘Honeycrisp’ reveals hormonal crosstalk and reduced cell-wall remodelling in the fruit-abscission zone

Apples (Malus domestica Borkh) are prone to pre-harvest fruit drop which is more pronounced in ‘Honeycrisp’. Using a transcriptomic approach, we analyzed the molecular mechanisms of fruit retention in ‘Honeycrisp’. A total of 726 differentially expressed genes (DEGs) were identified in the abscission zone of hexanal-treated and untreated fruit (FAZ). Hexanal down-regulated the genes involved in ethylene biosynthesis, such as S-adenosylmethionine synthase (SAM2) and 1-aminocyclopropane-1carboxylic acid oxidases (ACO3, ACO4 and ACO4-like). Genes related to ABA biosynthesis (FDPS and CLE25) were also down-regulated. On the contrary, gibberellic acid (GA) biosynthesis genes, gibberellin 20 oxidase1-like (GA20OX-like) and ent-kaurene oxidase (KO) were up-regulated. Further, hexanal down-regulated the expression of genes related to cell-wall remodelling enzymes such as polygalacturonase (PG1), glucanases (endo-β-1,4-glucanase; EG) and expansins (EXPA1-like, EXPA6, EXPA8, EXPA10-like, EXPA16-like). Hexanal also reduced ethylene, and abscisic acid (ABA) production at commercial harvest stage. Hexanal reduced ethylene production in fruits and thus reduced the sensitivity of FAZ cells to ethylene and ABA. Simultaneously, hexanal maintained the cell-wall integrity of FAZ cells by regulating genes involved in cell-wall modifications. Our findings show that fruit abscission is delayed by hexanal, by down regulating ABA through an ethylene-dependent mechanism. Highlight Hexanal, a naturally occurring plant compound, increased fruit retention in apples by decreasing ethylene and ABA production and maintaining the cell-wall integrity in the fruit abscission zone.
Mitochondria serve as axonal shuttle for Cox7c mRNA through mechanism that involves its mitochondrial targeting signal

Localized protein synthesis plays a key role in spatiotemporal regulation of the cellular proteome. Neurons, which extend axons over long distances, heavily depend on this process. However, the mechanisms by which axonal mRNAs are transported to protein target sites are not fully understood. Here, we describe a novel role for mitochondria in shuttling a nuclear encoded mRNA along axons. Fractionation analysis and smFISH revealed that the mRNA encoding Cox7c protein is preferentially associated with mitochondria from a neuronal cell line and from primary motor neuron axons. Live cell imaging of MS2-tagged Cox7c or Cryab control mRNA in primary motor neurons further confirmed the preferential colocalization of Cox7c mRNA with mitochondria. More importantly, Cox7c demonstrated substantial cotransport with mitochondria along axons. Intriguingly, the coding region, rather than the 3’UTR, was found to be the key domain for the cotransport. Furthermore, we show that puromycin treatment as well as hindering the synthesis of the mitochondrial targeting signal (MTS) reduced the colocalization. Overall, our results reveal a novel mRNA transport mode which exploits mitochondria as a shuttle and translation of the MTS as a recognition feature. Thus, mitochondria may play a role in spatial regulation of the axonal transcriptome and self-sustain their own proteome at distant neuronal sites.
Silencing long ascending propriospinal neurons after spinal cord injury improves hindlimb stepping in the adult rat

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. In uninjured animals, conditionally silencing LAPNs resulted in disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping in the adult rat. Given their ventrolateral location in the spinal cord white matter, many LAPN axons likely remain intact following thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would result in diminished hindlimb locomotor function. We found instead that silencing of spared LAPNs post-SCI restored the left-right hindlimb coordination associated with alternating gaits that was lost as a result of SCI. Several other fundamental characteristics of hindlimb stepping were also improved and the number of abnormal steps were reduced. However, hindlimb-forelimb coordination was not restored. These data suggest that the temporal information carried between the enlargements by the LAPNs after SCI may be detrimental to hindlimb locomotor function. These observations have implications for our understanding of the relationship between injury severity and functional outcome, for the efforts to develop neuro- and axo-protective therapeutic strategies, and also for the clinical study/implementation of spinal stimulation and neuromodulation.
Haplotype-aware inference of human chromosome abnormalities

Significance Whole-chromosome gains and losses (aneuploidies) are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8,154 in vitro fertilization (IVF) embryos. We reclassified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were previously hidden. Our method complements standard protocols for preimplantation genetic testing, while offering insight into the biology of early development. Extra or missing chromosomes—a phenomenon termed aneuploidy—frequently arise during human meiosis and embryonic mitosis and are the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing for aneuploidy (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy, may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05 × and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.
Progressive Increases in Mesenchymal Cell Diversity Modulate Lung Development and are Attenuated by Hyperoxia

Early in life, the lung mesenchyme is extremely dynamic. We profiled the transcriptomes and locations of mesenchymal cells (MC) in the perinatal murine lung and observed cellular progressions of fibroblasts, myofibroblasts, airway smooth muscle (ASM), and mural cells, poised to modulate the extracellular matrix (ECM) with both subtype- and temporal-specific patterns. Within one day after birth, embryonic fibroblast precursors branched into two subtypes, alveolar and adventitial fibroblasts. ASM and myofibroblasts derived from a common precursor population that specifically expressed Crh, a hormone central to glucocorticoid release. Vascular smooth muscle cells and pericytes differentiated gradually. Fibroblast, myofibroblast, and pericyte proliferation peaked at 7 days after birth. Paracrine signaling among cell types decreased after birth and was hierarchical, with pericytes at the interface between endothelial cells and other MC. Postnatal hyperoxia delayed the developmental progression in cell type abundance and gene expression, mirroring the arrested development that characterizes the neonatal lung disease, bronchopulmonary dysplasia. Hyperoxia decreased pericyte and myofibroblast abundances and proliferation, dysregulated signaling, altered ECM modulation and, in males specifically, gave rise to a novel population of contractile fibroblasts. This study identifies the mesenchymal populations orchestrating lung development at the critical transition to air-breathing life and their distinct reactions to hyperoxia.
V-ATPase is a universal regulator of LC3 associated phagocytosis and non-canonical autophagy

Non-canonical autophagy is a key cellular pathway in immunity, cancer and neurodegeneration, characterised by Conjugation of ATG8 to endolysosomal Single-Membranes (CASM). CASM is activated by engulfment (endocytosis, phagocytosis), agonists (STING, TRPML1) and infection (influenza), dependent on the ATG16L1 WD40-domain, and specifically K490. However, the factor(s) associated with non-canonical ATG16L1 recruitment, and CASM induction, remain unknown. Here, we investigate a role for V-ATPase during non-canonical autophagy. We report that increased V0-V1 engagement is associated with, and sufficient for, CASM activation. Upon V0-V1 binding, V-ATPase directly recruits ATG16L1, via K490, during LC3-associated phagocytosis (LAP), STING- and drug-induced CASM, indicating a common mechanism. Furthermore, during LAP, key molecular players, including NADPH oxidase/ROS, converge on V-ATPase. Finally, we show that LAP is sensitive to Salmonella SopF, which disrupts the V-ATPase-ATG16L1 axis, and provide evidence that CASM contributes to the Salmonella host response. Together, these data identify V-ATPase as a universal regulator of CASM, and indicate that SopF evolved in part to evade non-canonical autophagy.
Findings of the AmericasNLP 2021 Shared Task on Open Machine Translation for Indigenous Languages of the Americas

This paper presents the results of the 2021 Shared Task on Open Machine Translation for Indigenous Languages of the Americas. The shared task featured two independent tracks, and participants submitted machine translation systems for up to 10 indigenous languages. Overall, 8 teams participated with a total of 214 submissions. We provided training sets consisting of data collected from various sources, as well as manually translated sentences for the development and test sets. An official baseline trained on this data was also provided. Team submissions featured a variety of architectures, including both statistical and neural models, and for the majority of languages, many teams were able to considerably improve over the baseline. The best performing systems achieved 12.97 ChrF higher than baseline, when averaged across languages.