Miracle-dz/UniFAR-FTUs huggingface dataset:
Modular Organization of the NusA- and NusG-Stimulated RNA Polymerase Pause Signal That Participates in the Bacillus subtilis trp Operon Attenuation Mechanism

ABSTRACT The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism in which tryptophan-activated TRAP binds to the nascent transcript and blocks the formation of an antiterminator structure such that the formation of an overlapping intrinsic terminator causes termination in the 5′ untranslated region (5′ UTR). In the absence of bound TRAP, the antiterminator forms and transcription continues into the trp genes. RNA polymerase pauses at positions U107 and U144 in the 5′ UTR. The general transcription elongation factors NusA and NusG stimulate pausing at both positions. NusG-stimulated pausing at U144 requires sequence-specific contacts with a T tract in the nontemplate DNA (ntDNA) strand within the paused transcription bubble. Pausing at U144 participates in a trpE translation repression mechanism. Since U107 just precedes the critical overlap between the antiterminator and terminator structures, pausing at this position is thought to participate in attenuation. Here we carried out in vitro pausing and termination experiments to identify components of the U107 pause signal and to determine whether pausing affects the termination efficiency in the 5′ UTR. We determined that the U107 and U144 pause signals are organized in a modular fashion containing distinct RNA hairpin, U-tract, and T-tract components. NusA-stimulated pausing was affected by hairpin strength and the U-tract sequence, whereas NusG-stimulated pausing was affected by hairpin strength and the T-tract sequence. We also determined that pausing at U107 results in increased TRAP-dependent termination in the 5′ UTR, implying that NusA- and NusG-stimulated pausing participates in the trp operon attenuation mechanism by providing additional time for TRAP binding. IMPORTANCE The expression of several bacterial operons is controlled by regulated termination in the 5′ untranslated region (5′ UTR). Transcription attenuation is defined as situations in which the binding of a regulatory molecule promotes transcription termination in the 5′ UTR, with the default being transcription readthrough into the downstream genes. RNA polymerase pausing is thought to participate in several attenuation mechanisms by synchronizing the position of RNA polymerase with RNA folding and/or regulatory factor binding, although this has only been shown in a few instances. We found that NusA- and NusG-stimulated pausing participates in the attenuation mechanism controlling the expression of the Bacillus subtilis trp operon by increasing the TRAP-dependent termination efficiency. The pause signal is organized in a modular fashion containing RNA hairpin, U-tract, and T-tract components.
Spread of Plasmid-Encoded NDM-1 and GES-5 Carbapenemases among Extensively Drug-Resistant and Pandrug-Resistant Clinical Enterobacteriaceae in Durban, South Africa

ABSTRACT Whole-genome sequence analyses revealed the presence of blaNDM-1 (n = 31), blaGES-5 (n = 8), blaOXA-232 (n = 1), or blaNDM-5 (n = 1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae organisms isolated from in-patients in 10 private hospitals (2012 to 2013) in Durban, South Africa. Two novel NDM-1-encoding plasmids from Klebsiella pneumoniae were circularized by PacBio sequencing. In p19-10_01 [IncFIB(K); 223.434 bp], blaNDM-1 was part of a Tn1548-like structure (16.276 bp) delineated by IS26. The multireplicon plasmid p18-43_01 [IncR_1/IncFIB(pB171)/IncFII(Yp); 212.326 bp] shared an 80-kb region with p19-10_01, not including the blaNDM-1-containing region. The two plasmids were used as references for tracing NDM-1-encoding plasmids in the other genome assemblies. The p19-10_01 sequence was detected in K. pneumoniae (n = 7) only, whereas p18-43_01 was tracked to K. pneumoniae (n = 4), Klebsiella michiganensis (n = 1), Serratia marcescens (n = 11), Enterobacter spp. (n = 7), and Citrobacter freundii (n = 1), revealing horizontal spread of this blaNDM-1-bearing plasmid structure. Global phylogeny showed clustering of the K. pneumoniae (18/20) isolates together with closely related carbapenemase-negative ST101 isolates from other geographical origins. The South African isolates were divided into three phylogenetic subbranches, where each group had distinct resistance and replicon profiles, carrying either p19-10_01, p18-10_01, or pCHE-A1 (8,201 bp). The latter plasmid carried blaGES-5 and aacA4 within an integron mobilization unit. Our findings imply independent plasmid acquisition followed by local dissemination. Additionally, we detected blaOXA-232 carried by pPKPN4 in K. pneumoniae (ST14) and blaNDM-5 contained by a pNDM-MGR194-like genetic structure in Escherichia coli (ST167), adding even more complexity to the multilayer molecular mechanisms behind nosocomial spread of carbapenem-resistant Enterobacteriaceae in Durban, South Africa.
Is there a rural/urban gap in the quality of HIV care for treatment-naïve HIV-positive individuals initiating antiretroviral therapy in British Columbia?

ABSTRACT Rurally located people living with HIV (PLWH) face unique challenges associated with remoteness that may negatively affect their HIV care outcomes. The Programmatic Compliance Score (PCS) has been used previously as a quality of care metric, and is predictive of mortality for treatment-naïve individuals initiating combination antiretroviral therapy (cART). This study looked at whether the rurality of PLWH impacted their PCS. PCS was calculated for PLWH (≥19 years old) initiating cART in British Columbia between 2000 and 2013. Rurality was determined at the time of cART initiation using two methodologies: (1) a categorical postal code method; and (2) the General Practice Rurality Index (GPRI), a score representing an individual’s degree of rurality. Ordinal logistic regression modeling was used to assess the relationship between rurality and PCS. Among 4616 PLWH with an evaluable PCS, 176 were classified as rural and 3512 as urban (928 had an unknown postal code). After adjusting for age, sex, hepatitis C status, Indigenous ancestry, and year of cART initiation, categorical rurality was not associated with a worse PCS (adjusted odds ratio (AOR) 1.04; 95% CI: 0.77–1.39). However, an increasing degree of rurality was associated with a worse PCS (AOR (per 10 increase in GPRI) 1.13; 95% CI: 1.06–1.20). Given that a poor PCS has been shown to be predictive of all-cause mortality for individuals initiating cART, strategies to improve access to HIV care for rural individuals should be evaluated.
Preventive oral health intervention among old home care clients

Background poor oral health is common among older people dependent on supportive care and it affects their quality of life. Cognitive impairment and functional dependency may increase the risk of compromised daily oral hygiene. Aim to investigate the effectiveness of a tailored preventive oral health intervention among home care clients aged 75 years or over. Patients and methods the intervention group comprised 151 patients (84.4 ± 5.6 years) and the control group 118 patients (84.7 ± 5.2 years). An interview and a clinical examination were carried out before a tailored intervention of oral and denture hygiene. The participants in both groups were re-interviewed and re-examined after 6 months. Results the intervention significantly reduced the number of plaque covered teeth and improved denture hygiene. In addition, functional ability and cognitive function were significantly associated with better oral hygiene. Conclusions the intervention had a positive effect on oral hygiene, however the number of teeth with plaque remained high, even after the intervention. Multiple approaches based on individual needs are required to improve the oral health of vulnerable older adults, including integrating dental preventive care into daily care plan carried out by home care nurses.
Auditory stimulation of sleep slow oscillations modulates subsequent memory encoding through altered hippocampal function

Abstract Study Objectives Slow oscillations (SO) during sleep contribute to the consolidation of learned material. How the encoding of declarative memories during subsequent wakefulness might benefit from their enhancement during sleep is less clear. In this study, we investigated the impact of acoustically enhanced SO during a nap on subsequent encoding of declarative material. Methods Thirty-seven healthy young adults were studied under two conditions: stimulation (STIM) and no stimulation (SHAM), in counter-balanced order following a night of sleep restriction (4 hr time-in-bed [TIB]). In the STIM condition, auditory tones were phase-locked to the SO up-state during a 90 min nap opportunity. In the SHAM condition, corresponding time points were marked but tones were not presented. Thirty minutes after awakening, participants encoded pictures while undergoing fMRI. Picture recognition was tested 60 min later. Results Acoustic stimulation augmented SO across the group, but there was no group level benefit on memory. However, the magnitude of SO enhancement correlated with greater recollection. SO enhancement was also positively correlated with hippocampal activation at encoding. Although spindle activity increased, this did not correlate with memory benefit or shift in hippocampal signal. Conclusions Acoustic stimulation during a nap can benefit encoding of declarative memories. Hippocampal activation positively correlated with SO augmentation.
Association between junk food consumption and fast-food outlet access near school among Quebec secondary-school children: findings from the Quebec Health Survey of High School Students (QHSHSS) 2010–11

Abstract Objective We investigated the association between junk food consumption at lunchtime (JCL) and fast-food outlet access near school among secondary-school children in Quebec. Design A geographic information system database was used to characterize the food environment around a sub-sample of 374 public schools in which 26 655 students were enrolled. The outcome variable was JCL during the previous week, dichotomized into low JCL (none or once) v. high JCL (twice or more). Access to fast-food outlets near school was assessed using an existing database of fast-food outlets in Quebec. Covariates included student (age, sex and self-rated perceived health), family (familial status and parental education) and school (urban/rural status and deprivation) variables. Hierarchical logistic regression models were employed for analyses using PROC GLIMMIX of SAS version 9.3. Setting Province of Quebec, Canada. Subjects We used data from the Quebec Health Survey of High School Students (QHSHSS) 2010–11, a survey of secondary-school Quebec students. Results Exposure to two or more fast-food outlets within a radius of 750 m around schools was associated with a higher likelihood of excess JCL (OR=1·50; 95 % CI 1·28, 1·75), controlling for the characteristics of the students, their families and their schools. Conclusions The food environment surrounding schools can constitute a target for interventions to improve food choices among secondary-school children living in the province of Quebec. Transforming environments around schools to promote healthy eating includes modifying zoning regulations that restrict access to fast-food outlets around schools.
Does the projected pathway to global warming targets matter?

Since the ‘Paris agreement’ in 2015 there has been much focus on what a +1.5 °C or +2 °C warmer world would look like. Since the focus lies on policy relevant global warming targets, or specific warming levels (SWLs), rather than a specific point in time, projections are pooled together to form SWL ensembles based on the target temperature rather than emission scenario. This study uses an ensemble of CMIP5 global model projections to analyse how well SWL ensembles represent the stabilized climate of global warming targets. The results show that the SWL ensembles exhibit significant trends that reflect the transient nature of the RCP scenarios. These trends have clear effect on the timing and clustering of monthly cold and hot extremes, even though the effect on the temperature of the extreme months is less visible. In many regions there is a link between choice of RCP scenario used in the SWL ensemble and climate change signal in the highest monthly temperatures. In other regions there is no such clear-cut link. From this we conclude that comprehensive analyses of what prospects the different global warming targets bring about will require stabilization scenarios. Awaiting such targeted scenarios we suggest that prudent use of SWL scenarios, taking their characteristics and limitations into account, may serve as reasonable proxies in many situations.
Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis

Human endogenous retroviruses (HERVs) are remnants of retroviral germ line infections of human ancestors and make up ~8% of the human genome. Under physiological conditions, these elements are frequently inactive or non-functional due to deactivating mutations and epigenetic control. However, they can be reactivated under certain pathological conditions and produce viral transcripts and proteins. Several disorders, like multiple sclerosis or amyotrophic lateral sclerosis are associated with increased HERV expression. Although their detailed contribution to individual diseases has yet to be elucidated, an increasing number of studies in vitro and in vivo suggest HERVs as potent modulators of the immune system. They are able to affect the transcription of other immune-related genes, interact with pattern recognition receptors, and influence the positive and negative selection of developing thymocytes. Interestingly, HERV envelope proteins can both stimulate and suppress immune responses based on different mechanisms. In the light of HERV proteins becoming an emerging drug target for autoimmune-related disorders and cancer, we will provide an overview on recent findings of the complex interactions between HERVs and the human immune system with a focus on autoimmunity.
Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer–Associated R438W DNA Polymerase Lambda Protein

Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol λ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol λ was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol λ in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen was assessed as it is commonly used in hormone replacement therapies and is a known breast cancer risk factor. Interestingly, the combination of estrogen treatment and the expression of the R438W Pol λ SNP drastically accelerated the rate of transformation. Estrogen exposure produces 8-oxoguanine lesions that persist in cells expressing R438W Pol λ compared with wild-type (WT) Pol λ–expressing cells. Unlike WT Pol λ, which performs error-free bypass of 8-oxoguanine lesions, expression of R438W Pol λ leads to an increase in mutagenesis and replicative stress in cells treated with estrogen. Together, these data suggest that individuals who carry the rs3730477 POLL germline variant have an increased risk of estrogen-associated breast cancer. Implications: The Pol λ R438W mutation can serve as a biomarker to predict cancer risk and implicates that treatment with estrogen in individuals with this mutation may further increase their risk of breast cancer. Mol Cancer Res; 14(11); 1068–77. ©2016 AACR.
The P450 CYP6Z1 confers carbamate/pyrethroid cross‐resistance in a major African malaria vector beside a novel carbamate‐insensitive N485I acetylcholinesterase‐1 mutation

Carbamates are increasingly used for vector control notably in areas with pyrethroid resistance. However, a cross‐resistance between these insecticides in major malaria vectors such as Anopheles funestus could severely limit available resistance management options. Unfortunately, the molecular basis of such cross‐resistance remains uncharacterized in An. funestus, preventing effective resistance management. Here, using a genomewide transcription profiling, we revealed that metabolic resistance through upregulation of cytochrome P450 genes is driving carbamate resistance. The P450s CYP6P9a, CYP6P9b and CYP6Z1 were the most upregulated detoxification genes in the multiple resistant mosquitoes. However, in silico docking simulations predicted CYP6Z1 to metabolize both pyrethroids and carbamates, whereas CYP6P9a and CYP6P9b were predicted to metabolize only the pyrethroids. Using recombinant enzyme metabolism and inhibition assays, we demonstrated that CYP6Z1 metabolizes bendiocarb and pyrethroids, whereas CYP6P9a and CYP6P9b metabolize only the pyrethroids. Other upregulated gene families in resistant mosquitoes included several cuticular protein genes suggesting a possible reduced penetration resistance mechanism. Investigation of the target‐site resistance in acetylcholinesterase 1 (ace‐1) gene detected and established the association between the new N485I mutation and bendiocarb resistance (odds ratio 7.3; P < 0.0001). The detection of multiple haplotypes in single mosquitoes after cloning suggested the duplication of ace‐1. A TaqMan genotyping of the N485I in nine countries revealed that the mutation is located only in southern Africa with frequency of 10–15% suggesting its recent occurrence. These findings will help in monitoring the spread and evolution of carbamate resistance and improve the design of effective resistance management strategies to control this malaria vector.
In silico characterization of tandem repeats in Trichophyton rubrum and related dermatophytes provides new insights into their role in pathogenesis

Abstract Trichophyton rubrum is the most common etiological agent of dermatophytoses worldwide, which is able to degrade keratinized tissues. The sequencing of the genome of different dermatophyte species has provided a large amount of data, including tandem repeats that may play a role in genetic variability and in the pathogenesis of these fungi. Tandem repeats are adjacent DNA sequences of 2–200 nucleotides in length, which exert regulatory and adaptive functions. These repetitive DNA sequences are found in different classes of fungal proteins, especially those involved in cell adhesion, a determinant factor for the establishment of fungal infection. The objective of this study was to develop a Dermatophyte Tandem Repeat Database (DTRDB) for the storage and identification of tandem repeats in T. rubrum and six other dermatophyte species. The current version of the database contains 35 577 tandem repeats detected in 16 173 coding sequences. The repeats can be searched using entry parameters such as repeat unit length (nt—nucleotide), repeat number, variability score, and repeat sequence motif. These data were used to study the relative frequency and distribution of repeats in the sequences, as well as their possible functions in dermatophytes. A search of the database revealed that these repeats occur in 22–33% of genes transcribed in dermatophytes where they could be involved in the success of adaptation to the host tissue and establishment of infection. The repeats were detected in transcripts that are mainly related to three biological processes: regulation, adhesion, and metabolism. The database developed enables users to identify and analyse tandem repeat regions in target genes related to pathogenicity and fungal–host interactions in dermatophytes and may contribute to the discovery of new targets for the development of antifungal agents. Database URL: http://comp.mch. ifsuldeminas.edu. br/dtrdb/
Hybrid GMR Sensor Detecting 950 pT/sqrt(Hz) at 1 Hz and Room Temperature

Advances in the magnetic sensing technology have been driven by the increasing demand for the capability of measuring ultrasensitive magnetic fields. Among other emerging applications, the detection of magnetic fields in the picotesla range is crucial for biomedical applications. In this work Picosense reports a millimeter-scale, low-power hybrid magnetoresistive-piezoelectric magnetometer with subnanotesla sensitivity at low frequency. Through an innovative noise-cancelation mechanism, the 1/f noise in the MR sensors is surpassed by the mechanical modulation of the external magnetic fields in the high frequency regime. A modulation efficiency of 13% was obtained enabling a final device’s sensitivity of ~950 pT/Hz1/2 at 1 Hz. This hybrid device proved to be capable of measuring biomagnetic signals generated in the heart in an unshielded environment. This result paves the way for the development of a portable, contactless, low-cost and low-power magnetocardiography device.
Characterization of Condensed Tannins from Purple Prairie Clover (Dalea purpurea Vent.) Conserved as either Freeze-Dried Forage, Sun-Cured Hay or Silage

Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the concentration, chemical composition and biological activity of CT. Whole-plant purple prairie clover (PPC, Dalea purpurea Vent.) was harvested at full flower and conserved as freeze-dried forage (FD), hay (HAY) or silage (SIL). Concentration of CT in conserved PPC was determined by the butanol-HCl-acetone method. Structural composition, protein-precipitation capacity and anti-bacterial activity of CT isolated from conserved forage were determined by in situ thiolytic degradation followed by HPLC-MS analysis, a protein precipitation assay using bovine serum albumin and ribulose 1,5-disphosphate carboxylase as model proteins and by an Escherichia coli (E. coli) growth test, respectively. Conservation method had no effect on concentration of total CT, but ensiling decreased (p < 0.001) extractable CT and increased (p < 0.001) protein- and fiber-bound CT. In contrast, hay-making only increased (p < 0.01) protein-bound CT. Regardless of conservation method, epigallocatechin (EGC), catechin (C) and epicatechin (EC) were the major flavan-3-ol units, and gallocatechin (GC) was absent from both terminal and extension units of PPC CT. The SIL CT had the lowest (p < 0.001) EGC, but the highest (p < 0.01) EC in the extension units. Similarly, SIL CT exhibited a lower (p < 0.001) mean degree of polymerization (mDP), but higher (p < 0.001) procyanidins (PC) than FD or HAY CT. The protein-precipitating capacity of CT in conserved PPC ranked (p < 0.001) as FD > HAY > SIL. E. coli growth n M9 medium was inhibited by 25–100 µg/mL of CT isolated from FD, HAY and SIL (p < 0.05), but preservation method had no effect on the ability of CT to inhibit bacterial growth. The results demonstrated that ensiling decreased the extractability and protein-precipitating capacity of CT by increasing the proportions of PC. Purple prairie clover conserved as hay retained more biologically active CT than if it was conserved as silage.