Miracle-dz/UniFAR-FTUs huggingface dataset:
NusG-Dependent RNA Polymerase Pausing and Tylosin-Dependent Ribosome Stalling Are Required for Tylosin Resistance by Inducing 23S rRNA Methylation in Bacillus subtilis

Antibiotic resistance is a growing health concern. Resistance mechanisms have evolved that provide bacteria with a growth advantage in their natural habitat such as the soil. We determined that B. subtilis, a Gram-positive soil organism, has a mechanism of resistance to tylosin, a macrolide antibiotic commonly used in the meat industry. Tylosin induces expression of yxjB, which encodes an enzyme that methylates 23S rRNA. YxjB-dependent methylation of 23S rRNA confers tylosin resistance. NusG-dependent RNA polymerase pausing and tylosin-dependent ribosome stalling induce yxjB expression, and hence tylosin resistance, by preventing transcription termination upstream of the yxjB coding sequence and by preventing repression of yxjB translation. ABSTRACT Macrolide antibiotics bind to 23S rRNA within the peptide exit tunnel of the ribosome, causing the translating ribosome to stall when an appropriately positioned macrolide arrest motif is encountered in the nascent polypeptide. Tylosin is a macrolide antibiotic produced by Streptomyces fradiae. Resistance to tylosin in S. fradiae is conferred by methylation of 23S rRNA by TlrD and RlmAII. Here, we demonstrate that yxjB encodes RlmAII in Bacillus subtilis and that YxjB-specific methylation of 23S rRNA in the peptide exit tunnel confers tylosin resistance. Growth in the presence of subinhibitory concentrations of tylosin results in increased rRNA methylation and increased resistance. In the absence of tylosin, yxjB expression is repressed by transcription attenuation and translation attenuation mechanisms. Tylosin-dependent induction of yxjB expression relieves these two repression mechanisms. Induction requires tylosin-dependent ribosome stalling at an RYR arrest motif at the C terminus of a leader peptide encoded upstream of yxjB. Furthermore, NusG-dependent RNA polymerase pausing between the leader peptide and yxjB coding sequences is essential for tylosin-dependent induction. Pausing synchronizes the position of RNA polymerase with ribosome position such that the stalled ribosome prevents transcription termination and formation of an RNA structure that sequesters the yxjB ribosome binding site. On the basis of our results, we are renaming yxjB as tlrB. IMPORTANCE Antibiotic resistance is a growing health concern. Resistance mechanisms have evolved that provide bacteria with a growth advantage in their natural habitat such as the soil. We determined that B. subtilis, a Gram-positive soil organism, has a mechanism of resistance to tylosin, a macrolide antibiotic commonly used in the meat industry. Tylosin induces expression of yxjB, which encodes an enzyme that methylates 23S rRNA. YxjB-dependent methylation of 23S rRNA confers tylosin resistance. NusG-dependent RNA polymerase pausing and tylosin-dependent ribosome stalling induce yxjB expression, and hence tylosin resistance, by preventing transcription termination upstream of the yxjB coding sequence and by preventing repression of yxjB translation.
Computer Assisted Annotation of Tension Development in TED Talks through Crowdsourcing

We propose a method of machine-assisted annotation for the identification of tension development, annotating whether the tension is increasing, decreasing, or staying unchanged. We use a neural network based prediction model, whose predicted results are given to the annotators as initial values for the options that they are asked to choose. By presenting such initial values to the annotators, the annotation task becomes an evaluation task where the annotators inspect whether or not the predicted results are correct. To demonstrate the effectiveness of our method, we performed the annotation task in both in-house and crowdsourced environments. For the crowdsourced environment, we compared the annotation results with and without our method of machine-assisted annotation. We find that the results with our method showed a higher agreement to the gold standard than those without, though our method had little effect at reducing the time for annotation. Our codes for the experiment are made publicly available.
Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington's disease mice.

Transcriptional and epigenetic alterations occur early in Huntington's disease (HD) and treatment with epigenetic modulators are beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise in multiple cancers and in neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5-11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent High Molecular Weight (HMW) species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.
Mast cell mediators in relation to dengue severity: A systematic review and meta‐analysis

Degranulation of mast cells (MCs) releases several mediators such as vascular endothelial growth factor (VEGF), chymase, tryptase, histamine, and cytokines, which all have important roles in the severity of dengue infection. We aimed to investigate the role of MCs in severity of dengue.
GABAergic changes in the thalamocortical circuit in Parkinson's disease

Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma‐aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine‐dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine‐resistant tremor (n = 17), dopamine‐responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA‐to‐total‐creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression.
Phosphatidylinositol 3‐kinase‐δ controls endoplasmic reticulum membrane fluidity and permeability in fungus‐induced allergic inflammation in mice

Phosphatidylinositol 3‐kinase (PI3K), especially PI3K‐δ, and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus through mechanisms that are not well understood. Here we have investigated these mechanisms, using BEAS‐2B human bronchial epithelial cells and a mouse model of A. fumigatus‐induced allergic lung inflammation.
Threat Anticipation in Pulvinar and in Superficial Layers of Primary Visual Cortex (V1). Evidence from Layer-Specific Ultra-High Field 7T fMRI

The perceptual system gives priority to threat-relevant signals with survival value. In addition to the processing initiated by sensory inputs of threat signals, prioritization of threat signals may also include processes related to threat anticipation. These neural mechanisms remain largely unknown. Using ultra-high-field 7 tesla (7T) fMRI, we show that anticipatory processing takes place in the early stages of visual processing, specifically in the pulvinar and V1. Abstract The perceptual system gives priority to threat-relevant signals with survival value. In addition to the processing initiated by sensory inputs of threat signals, prioritization of threat signals may also include processes related to threat anticipation. These neural mechanisms remain largely unknown. Using ultra-high-field 7 tesla (7T) fMRI, we show that anticipatory processing takes place in the early stages of visual processing, specifically in the pulvinar and V1. When anticipation of a threat-relevant fearful face target triggered false perception of not-presented target, there was enhanced activity in the pulvinar as well as in the V1 superficial-cortical-depth (layers 1–3). The anticipatory activity was absent in the LGN or higher visual cortical areas (V2–V4). The effect in V1 was specific to the perception of fearful face targets and did not generalize to happy face targets. A preliminary analysis showed that the connectivity between the pulvinar and V1 superficial-cortical-depth was enhanced during false perception of threat, indicating that the pulvinar and V1 may interact in preparation of anticipated threat. The anticipatory processing supported by the pulvinar and V1 may play an important role in non-sensory-input-driven anxiety states.
Cul3‐Klhl18 ubiquitin ligase modulates rod transducin translocation during light‐dark adaptation

Adaptation is a general feature of sensory systems. In rod photoreceptors, light‐dependent transducin translocation and Ca2+ homeostasis are involved in light/dark adaptation and prevention of cell damage by light. However, the underlying regulatory mechanisms remain unclear. Here, we identify mammalian Cul3‐Klhl18 ubiquitin ligase as a transducin translocation modulator during light/dark adaptation. Under dark conditions, Klhl18−/− mice exhibited decreased rod light responses and subcellular localization of the transducin α‐subunit (Tα), similar to that observed in light‐adapted Klhl18+/+ mice. Cul3‐Klhl18 promoted ubiquitination and degradation of Unc119, a rod Tα‐interacting protein. Unc119 overexpression phenocopied Tα mislocalization observed in Klhl18−/− mice. Klhl18 weakly recognized casein kinase‐2‐phosphorylated Unc119 protein, which is dephosphorylated by Ca2+‐dependent phosphatase calcineurin. Calcineurin inhibition increased Unc119 expression and Tα mislocalization in rods. These results suggest that Cul3‐Klhl18 modulates rod Tα translocation during light/dark adaptation through Unc119 ubiquitination, which is affected by phosphorylation. Notably, inactivation of the Cul3‐Klhl18 ligase and calcineurin inhibitors FK506 and cyclosporine A that are known immunosuppressant drugs repressed light‐induced photoreceptor damage, suggesting potential therapeutic targets.
Neural properties of fundamental function encoding of sound selectivity in the female avian auditory cortex

Zebra finches (Taeniopygia guttata) use their voices for communication. Song structures in the songs of individual males are important for sound recognition in females. The caudomedial mesopallium (CMM) and nidopallium (NCM) are known to be essential higher auditory regions for sound recognition. These two regions have also been discussed with respect to their fundamental functions and song selectivity. To clarify their functions and selectivity, we investigated latencies and spiking patterns and also developed a novel correlation analysis to evaluate the relationship between neural activity and the characteristics of acoustic factors. We found that the latencies and spiking patterns in response to song stimuli differed between the CMM and NCM. In addition, our correlation analysis revealed that amplitude and frequency structures were important temporal acoustic factors for both regions. Although the CMM and NCM have different fundamental functions, they share similar encoding systems for acoustic factors.
Prediagnostic Allostatic Load as a Predictor of Poorly Differentiated and Larger Sized Breast Cancers among Black Women in the Women's Circle of Health Follow-Up Study

Background: Few studies have empirically tested the association of allostatic load (AL) with breast cancer clinicopathology. The aim of this study was to examine the association of AL, measured using relevant biomarkers recorded in medical records before breast cancer diagnosis, with unfavorable tumor clinicopathologic features among Black women. Methods: In a sample of 409 Black women with nonmetastatic breast cancer who are enrolled in the Women's Circle of Health Follow-Up Study, we estimated prediagnostic AL using two measures: AL measure 1 [lipid profile–based—assessed by systolic and diastolic blood pressure (SBP, DBP), high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, and glucose levels; waist circumference; and use of diabetes, hypertension, or hypercholesterolemia medication] and AL measure 2 (inflammatory index–based—assessed by SBP, DBP, glucose, and albumin levels; estimated glomerular filtration rate; body mass index; waist circumference; and use of medications previously described). We used Cohen's statistic to assess agreement between the two AL measures and multivariable logistic models to assess the associations of interest. Results: AL measures 1 and 2 moderately agreed (κ = 0.504). Higher prediagnostic AL predicted higher grade (poorly differentiated vs. well/moderately differentiated) using AL measure 1 [OR = 2.16; 95% confidence interval (CI), 1.18–3.94] and AL measure 2 (OR = 1.60; 95% CI, 1.02–2.51), and larger tumor size (≥2 cm vs. <2 cm; OR = 1.58; 95% CI, 1.01–2.46) using AL measure 2 only. Conclusions: Elevated prediagnostic AL might contribute to more unfavorable breast cancer clinicopathology. Impact: Addressing elevated prediagnostic levels of AL has potentially important clinical implications.
Developing a Model of Care for Home Infusions of Natalizumab for People With Multiple Sclerosis

Natalizumab is an effective treatment for multiple sclerosis that requires 4-weekly infusions that are usually provided in hospital outpatient clinics. In this study, a model of care (MOC), an overarching design for the provision of a health care service, was developed to permit home infusions of natalizumab. The proposed new MOC comprised 9 dimensions, in addition to the central concept of patient-centered care at home. The new MOC is responsive to patient needs and prioritizes the nurse–patient therapeutic relationship. It provides practical examples of patient-centered care to guide clinical practice for this patient population in the home setting.
The Impact of Acoustic Clutter on Large Array Abdominal Imaging

Abdominal imaging suffers from a particularly difficult acoustic environment—targets are located deep and overlying tissue layers with varying properties generate acoustic clutter. Increasing array size can overcome the penetration and lateral resolution problems in ideal conditions, but how the impact of clutter scales with increasing array extent is unknown and may limit the benefits in vivo. Previous ex vivo experimental work showed the promise of large arrays but was technically limited to a length of 6.4 cm and to only partial sampling of the array elements. We present an extension of those studies using the Fullwave simulation tool to create a 10 cm $\times 2$ cm matrix array with full lateral element sampling. We used a numerical model of the abdomen based on the maps of tissue acoustical properties and found that propagation through the modeled abdominal layers generated on average 25.4 ns of aberration and 0.74 cm of reverberation clutter across the array extent. Growing the full aperture from 2 to 10 cm improved contrast by 8.6 dB and contrast-to-noise ratio by 22.9% in addition to significantly improving target resolution. Alternative array strategies that may be useful for implementation—mismatched aperture sizes or a swept synthetic aperture—also produced improved quality with growing aperture size. These results motivate the development of larger diagnostic imaging arrays for the purpose of high-resolution imaging in challenging environments.
Speech perception, real-ear measurements and self-perceived hearing impairment after remote and face-to-face programming of hearing aids: A randomized single-blind agreement study

Introduction Current literature does not provide strong evidence that remote programming of hearing aids is effective, despite its increasing use by audiologists. We tested speech perception outcomes, real-ear insertion gain, and changes in self-perceived hearing impairment after face-to-face and remote programming of hearing aids in a randomized multicentre, single-blind crossover study. Methods Adult experienced hearing aid users were enrolled during routine follow-up visits to audiology clinics. Hearing aids were programmed both face to face and remotely, then participants randomly received either the face-to-face or remote settings in a blinded manner and were evaluated 5 weeks later. Participants then received the other settings and were evaluated 5 weeks later. Results Data from 52 out of 60 participants were analysed. We found excellent concordance in performance of hearing aids programmed face to face and remotely for speech understanding in quiet (phonetically balanced kindergarten test – intraclass correlation coefficient of 0.92 (95% confidence interval: 0.87–0.95)), and good concordance in performance for speech understanding in noise (phonetically balanced kindergarten +5 dB signal-to-noise ratio – intraclass correlation coefficient of 0.71 (95% confidence interval: 0.55–0.82)). Face-to-face and remote programming took 10 minutes (±2.9) and 10 minutes (±2.8), respectively. Real-ear insertion gains were highly correlated for input sound at 50, 65 and 80 dB sound pressure levels. The programming type did not affect the abbreviated profile of hearing aid questionnaire scores. Conclusions In experienced hearing aid users, face-to-face and remote programming of hearing aids give similar results in terms of speech perception, with no increase in the time spent on patients’ care and no difference in self-reported hearing benefit. ClinicalTrials.gov Identifier NCT02589561
Dissipation Theory-Based Ecological Protection and Restoration Scheme Construction for Reclamation Projects and Adjacent Marine Ecosystems

According to the 2017 results of the Special Inspector of Sea Reclamation, a substantial number of idle reclamation zones existed in 11 provinces (cities) along the coast of China. To improve the protection level of coastal wetlands and strictly control reclamation activities, it is necessary to carry out ecological restoration of reclamation projects and adjacent marine ecosystems. The characteristics of Guanghai Bay and its reclamation project are typical in China’s coastal areas, making it an optimal representative site for this study. The dissipative structure and entropy theory was used to analyze ecological problems and environmental threats. The analytic hierarchy process was applied to determine the order of the negative entropy flow importance. The entropy increase and decrease mechanism was used to determine an ecological protection and restoration scheme for the reclamation, including the reclamation of wetland resource restoration, shoreline landscape restoration, environmental pollution control, and marine biological resource restoration. Finally, based on system logic, a typical ecological restoration system was constructed east of Guanghai Bay, with the mangrove wetland area as the model in the north and the artificial sandbeach recreation area as the focus in the south.
Molecular Characterization of a Novel Cold-Active Hormone-Sensitive Lipase (HaHSL) from Halocynthiibacter Arcticus

Bacterial hormone-sensitive lipases (bHSLs), which are homologous to the catalytic domains of human HSLs, have received great interest due to their uses in the preparation of highly valuable biochemicals, such as drug intermediates or chiral building blocks. Here, a novel cold-active HSL from Halocynthiibacter arcticus (HaHSL) was examined and its enzymatic properties were investigated using several biochemical and biophysical methods. Interestingly, HaHSL acted on a large variety of substrates including tertiary alcohol esters and fish oils. Additionally, this enzyme was highly tolerant to high concentrations of salt, detergents, and glycerol. Furthermore, immobilized HaHSL retained its activity for up to six cycles of use. Homology modeling suggested that aromatic amino acids (Trp23, Tyr74, Phe78, Trp83, and Phe245) in close proximity to the substrate-binding pocket were important for enzyme activity. Mutational analysis revealed that Tyr74 played an important role in substrate specificity, thermostability, and enantioselectivity. In summary, the current study provides an invaluable insight into the novel cold-active HaHSL from H. arcticus, which can be efficiently and sustainably used in a wide range of biotechnological applications.
A Randomized Controlled Trial

METHODS: We randomly assigned patients with unfulfilled immediate postpartum tubal ligation requests to standard scheduling after a postpartum office visit or an expedited process in which we scheduled the interval tubal ligation surgery before discharge from the hospital. The primary outcome was proportion of participants undergoing tubal contraceptive procedures within 6 months of delivery. Secondary outcomes included patient satisfaction with the scheduling process, repeat pregnancy rates, and surgical outcomes. We estimated that 122 patients (61 per group) would provide greater than 80% power to identify a 25% difference favoring expedited scheduling in the primary outcome (one-sided a of 0.05).