Miracle-dz/UniFAR-FTUs huggingface dataset:
Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy

All bacterial cells must duplicate their genomes prior to dividing into two identical daughter cells. Chromosome replication is triggered when a nucleoprotein complex, termed the orisome, assembles, unwinds the duplex DNA, and recruits the proteins required to establish new replication forks. Obviously, the initiation of chromosome replication is essential to bacterial reproduction, but this process is not inhibited by any of the currently-used antimicrobial agents. Given the urgent need for new antibiotics to combat drug-resistant bacteria, it is logical to evaluate whether or not unexploited bacterial processes, such as orisome assembly, should be more closely examined for sources of novel drug targets. This review will summarize current knowledge about the proteins required for bacterial chromosome initiation, as well as how orisomes assemble and are regulated. Based upon this information, we discuss current efforts and potential strategies and challenges for inhibiting this initiation pharmacologically.
Association between PPARGC1A single nucleotide polymorphisms and increased risk of nonalcoholic fatty liver disease among Iranian patients with type 2 diabetes mellitus

Background/aim Environmental and genetic factors may play a major role in the development of nonalcoholic fatty liver disease (NAFLD) among people with obesity and type 2 diabetes mellitus. Based on the fact that PGC-1α, as the protein encoded by the PPARGC1A gene, plays a key role in energy metabolism pathways, it has been hypothesized that polymorphisms within the PPARGC1A gene may be associated with increased risks of NAFLD. Thus, this study was designed to evaluate the Gly482Ser polymorphism (rs8192678) within the PPARGC1A gene and its association with the increased risk of NAFLD in Iranian patients with type 2 diabetes. Materials and methods A total of 145 NAFLD patients with a history of type 2 diabetes and 145 healthy control subjects were included in the study. Gly482Ser polymorphism genotyping was done using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Results The results showed a significant difference between the PPARGC1A Gly482Ser polymorphism in NAFLD patients and the healthy controls. Accordingly, the AA genotype and A allele were increased in the NAFLD patients when compared to the healthy controls. However, no significant correlation was observed between the Gly482Ser polymorphism and the physiological and biochemical parameters. Conclusion Based on the results, the AA genotype, which is associated with the insertion of Ser, can be considered as a risk factor for the development of NAFLD in Iranian patients with diabetes type 2.
Investigating the Relationship Between Type 2 Diabetes and Dementia Using Electronic Medical Records in the GoDARTS Bioresource

OBJECTIVE To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource. RESEARCH DESIGN AND METHODS GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and APOE4 genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death. RESULTS Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio [csHR] 1.46, 95% CI 1.31–1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution [sd]HR 1.26, 95% CI 1.13–1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high—positive predictive value (PPV) 86.4% and PPV 72.8%, respectively—and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12–1.34) but not vascular dementia (HR 1.02, 95% CI 0.91–1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92–3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87–1.18). CONCLUSIONS Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.
Circularization of flavivirus genomic RNA inhibits de novo translation initiation

Abstract Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA–RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.
Effect of General Warm-Up Plus Dynamic Stretching on Endurance Running Performance in Well-Trained Male Runners

ABSTRACT Purpose: The purpose of this study was to compare the acute effects of general warm-up (GWU) and GWU plus dynamic stretching (GWU + DS) on endurance running performance in well-trained male runners. Method: The endurance running performances of eight well-trained long-distance male runners were assessed on a treadmill after 2 types of intervention for 5 min after running on the treadmill at a velocity equivalent to 70% maximal oxygen uptake (V̇O2max) in each athlete for 15 min. The interventions were GWU and GWU + DS. In the GWU + DS intervention, dynamic stretching was performed for ten repetitions as quickly as possible for the five muscle groups of the lower extremities. The total duration of the dynamic stretching was 3 min and 45 s. Endurance running performance was assessed at 1 min 15 s after the dynamic stretching. The endurance running performance was evaluated by the time to exhaustion (TTE) during running at a velocity equivalent to 90% O2max in each athlete. Results: The TTE (640.6 ± 220.4 s) after GWU + DS intervention was significantly (d = 1.02, p = .03) shorter than that (760.6 ± 249.1 s) after GWU intervention. Conclusions: The results demonstrated that GWU + DS intervention impaired immediate endurance performance of running at a velocity equivalent to 90% O2max in well-trained male runners compared with GWU intervention. Thus, we are not able to recommend that well-trained runners and their coaches use the protocol for GWU + DS described in this study during actual warm-ups.
Validation of an LC-MS/MS Method for the Quantification of Caffeine and Theobromine Using Non-Matched Matrix Calibration Curve

Caffeine is one of the most widely consumed psycho-stimulants. The study of the beneficial effects of caffeine consumption to decrease the risk of developing several neuropsychiatric pathologies is receiving increasing attention. Thus, accurate and sensitive methods have been developed, mainly by LC-MS/MS, in order to quantify caffeine and its metabolites. These quantifications of caffeine and its metabolites by LC-MS/MS require a considerable effort to select or find a surrogate matrix, without the compounds of interest, to be used in the calibration curves. Thus, we evaluated the possibility of using calibration curves prepared in solvent instead of calibration curves prepared in human plasma. Results show that the calibration curves prepared in solvent and in human plasma were similar by comparing their slopes and interceptions, and the accuracy and precision were within the limits of acceptance for both calibration curves. This work demonstrates that, by using internal standards, it is possible to use a calibration curve in solvent instead of a calibration curve in plasma to perform an accurate and precise quantification of caffeine and theobromine.
Draft Genome Sequence of Massilia sp. Strain MC02, Isolated from a Sandy Loam Maize Soil

From farmed corn soil in California, we isolated and sequenced a new member of the genus Massilia, Massilia sp. strain MC02. Massilia sp. MC02 has an assembled draft genome of 5,023,356 bp with a total of 4,790 protein-encoding genes and 3,028 predicted proteins, 47 tRNA genes, and 2 rRNA operons. ABSTRACT From farmed corn soil in California, we isolated and sequenced a new member of the genus Massilia, Massilia sp. strain MC02. Massilia sp. MC02 has an assembled draft genome of 5,023,356 bp with a total of 4,790 protein-encoding genes and 3,028 predicted proteins, 47 tRNA genes, and 2 rRNA operons.
A Patient Portal Intervention for Menopause Knowledge and Shared Decision-Making.

Background: Menopause is a time often fraught with changes and symptoms, which may require difficult choices and decision-making. During this period, women would benefit from a better understanding and in-depth discussions with providers regarding menopause, associated conditions, and appropriate therapy. Patient portals offer a potential means to improve knowledge and shared decision-making (SDM) about menopause. Materials and Methods: This protocol article explores the feasibility of using the secure messaging (SM) function of the Veterans Affairs (VA) Patient Portal, "My HealtheVet" to implement an educational intervention and measure its impact on knowledge and SDM in the management of menopause. Results: This is a quality improvement pilot study in which women veterans of menopausal age in the Miami VA are offered an educational intervention via a patient portal, while women veterans in two neighboring VA facilities are not. Intervention participants receive weekly SMs with information on menopause symptoms, and treatment. After 6-months, all participants are surveyed on menopause knowledge, SDM, and satisfaction with the program. Conclusion: This study is among the first to assess the impact of an innovative patient portal intervention to improve knowledge and SDM between patients and providers regarding menopause. If successful, our program will add to the "meaningful use" of patient portals and offer a scalable and timely resource for SDM about menopause.
EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.
Comparative dynamics of tropomyosin in vertebrates and invertebrates

Tropomyosin (Tpm) is an extended α‐helical coiled‐coil homodimer that regulates actinomyosin interactions in muscle. Molecular simulations of four Tpms, two from the vertebrate class Mammalia (rat and pig), and two from the invertebrate class Malacostraca (shrimp and lobster), showed that despite extensive sequence and structural homology across metazoans, dynamic behavior—particularly long‐range structural fluctuations—were clearly distinct. Vertebrate Tpms were more flexible and sampled complex, multi‐state conformational landscapes. Invertebrate Tpms were more rigid, sampling a highly constrained harmonic landscape. Filtering of trajectories by principle component analysis into essential subspaces showed significant overlap within but not between phyla. In vertebrate Tpms, hinge‐regions decoupled long‐range interhelical motions and suggested distinct domains. In contrast, crustacean Tpms did not exhibit long‐range dynamic correlations—behaving more like a single rigid rod on the nanosecond time scale. These observations suggest there may be divergent mechanisms for Tpm binding to actin filaments, where conformational flexibility in mammalian Tpm allows a preorganized shape complementary to the filament surface, and where rigidity in the crustacean Tpm requires concerted bending and binding.
Engineering DNA recognition and allosteric response properties of TetR family proteins by using a module-swapping strategy

Abstract The development of synthetic biological systems requires modular biomolecular components to flexibly alter response pathways. In previous studies, we have established a module-swapping design principle to engineer allosteric response and DNA recognition properties among regulators in the LacI family, in which the engineered regulators served as effective components for implementing new cellular behavior. Here we introduced this protein engineering strategy to two regulators in the TetR family: TetR (UniProt Accession ID: P04483) and MphR (Q9EVJ6). The TetR DNA-binding module and the MphR ligand-binding module were used to create the TetR-MphR. This resulting hybrid regulator possesses DNA-binding properties of TetR and ligand response properties of MphR, which is able to control gene expression in response to a molecular signal in cells. Furthermore, we studied molecular interactions between the TetR DNA-binding module and MphR ligand-binding module by using mutant analysis. Together, we demonstrated that TetR family regulators contain discrete and functional modules that can be used to build biological components with novel properties. This work highlights the utility of rational design as a means of creating modular parts for cell engineering and introduces new possibilities in rewiring cellular response pathways.
Comprehensive analysis of five long noncoding RNAs expression as competing endogenous RNAs in regulating hepatoma carcinoma

Liver cancer is the most common cancer and is the epitome of a recalcitrant cancer. Increasing evidence shown that long noncoding RNAs (lncRNA) were associated with cancer‐related death and could function as a competing endogenous RNA (ceRNA). To explore regulatory roles and potential prognostic biomarkers of lncRNA for liver cancer, RNA‐sequencing expression data were downloaded from the TCGA database and GEO database. A total of 357 patients were randomly divided into a discovery group and a validation group, of which 313 patients can obtain clinical data. In discovery phrase, 58 lncRNAs, 16 miRNAs, and 34 mRNAs were screened to construct the ceRNA network based on 252 patients employed from discovery group. Univariate and multivariate Cox hazard regression analysis model revealed that five lncRNAs (AATK‐AS1, C10orf91, LINC00162, LINC00200, and LINC00501) from 58 lncRNAs were formulated to predict the overall survival (OS). We used the value of gene expression and regression coefficients to construct a risk score based on the five lncRNAs. Next, we validated our model in the GSE116174 dataset (n = 64) and the validation group (n = 94) from TCGA database. Subgroup analysis suggest that the five lncRNAs played critical parts in early stage in cancer from both discovery and validation groups. The five lncRNAs were also found to be associated with immune cells infiltration including CD4+ memory activated, NK cells activated and mast cells activated, then the results were also validated according to the validation group. Furthermore, KEGG pathway enrichment analysis showed that these nine coexpressed modules using the method of WGCNA, and many of these pathways are associated with the development and progression of disease. At last, the transcription factor binding sites (TFBS) of the five lncRNAs were predicted, which help us to understand the potential mechanism that the TFBS adjusted the ceRNA network. In summary, the ceRNA regulatory network may contribute to a better understanding of liver cancer mechanism and provide potential prognostic biomarkers and therapeutic targets.
BraggNet: integrating Bragg peaks using neural networks.

Neutron crystallography offers enormous potential to complement structures from X-ray crystallography by clarifying the positions of low-Z elements, namely hydrogen. Macromolecular neutron crystallography, however, remains limited, in part owing to the challenge of integrating peak shapes from pulsed-source experiments. To advance existing software, this article demonstrates the use of machine learning to refine peak locations, predict peak shapes and yield more accurate integrated intensities when applied to whole data sets from a protein crystal. The artificial neural network, based on the U-Net architecture commonly used for image segmentation, is trained using about 100 000 simulated training peaks derived from strong peaks. After 100 training epochs (a round of training over the whole data set broken into smaller batches), training converges and achieves a Dice coefficient of around 65%, in contrast to just 15% for negative control data sets. Integrating whole peak sets using the neural network yields improved intensity statistics compared with other integration methods, including k-nearest neighbours. These results demonstrate, for the first time, that neural networks can learn peak shapes and be used to integrate Bragg peaks. It is expected that integration using neural networks can be further developed to increase the quality of neutron, electron and X-ray crystallography data.
CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival.

Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor FLCN, regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacological inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation), and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncover a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells.
Ascoma genotyping and mating type analyses of mycorrhizas and soil mycelia of Tuber borchii in a truffle orchard established by mycelial inoculated plants.

Tuber borchii (the Bianchetto truffle) is a heterothallic Ascomycete living in symbiotic association with trees and shrubs. Maternal and paternal genotype dynamics have already been studied for the black truffles Tuber melanosporum and Tuber aestivum but not yet for T. borchii. In this study we analyzed maternal and paternal genotypes in the first truffle orchard realized with plants inoculated with five different T. borchii mycelia. Our aims were to test the persistence of the inoculated mycelia, if maternal and/or paternal genotypes correspond to inoculated mycelia and to assess the hermaphroditism of T. borchii. The mating type of each isolate as well as those of mycorrhizas, ascomata and extraradical soil mycelia was determined. Moreover, simple sequence repeat (SSR) profiles of maternal and paternal genotypes were assessed in 18 fruiting bodies to investigate the sexual behavior of this truffle. The maternal genotypes of the fruiting bodies corresponded to those of the inoculated mycelia with only two exceptions. This confirmed that the inoculated mycelia persisted 9 years after plantation. As regards paternal partner, only two had the same genotype as those of the inoculated mycelia, suggesting hermaphroditism. Most of the new paternal genotypes originated from a recombination of those of inoculated mycelia. This article is protected by copyright. All rights reserved.
A Demonstration Project for the Utility of Kinect-Based Educational Games to Benefit Motor Skills of Children with ASD

Motor disorders often accompany autism spectrum disorder (ASD), although they are not included in its diagnostic criteria. Slower motor development is evident in early childhood in this population, making early motor skills intervention advisable. As educational games and modern technology can represent new forms of treatment, this study evaluated four Kinect-based visuo-motor games called Fruits that were specially designed for this research. We sought to test whether children with ASD would show behavior changes during their game play and whether any effects would generalize to another game called Rackets. The study included 10 elementary school children with ASD, aged 9-13 years, who were divided into (a) an experimental group (n = 5) who, in addition to standard treatment, played Fruits once a week for a 5-week period and Rackets both before and after the 5-week period and (b) a control group (n = 5) who received only standard treatment during this period and also played Rackets before and after it. We found significant improvements in gross motor skills and successful generalization of acquired skills among children in the experimental group relative to the control group. The experimental group also showed an increase in positive emotions and a decrease in loss of attention while playing the games. These preliminary findings indicate a motor skill benefit for children with ASD who play Kinect-based educational games, but further research is needed to replicate and expand these findings with larger participant samples.