Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel ribozymes: discovery, catalytic mechanisms, and the quest to understand biological function

Abstract Small endonucleolytic ribozymes promote the self-cleavage of their own phosphodiester backbone at a specific linkage. The structures of and the reactions catalysed by members of individual families have been studied in great detail in the past decades. In recent years, bioinformatics studies have uncovered a considerable number of new examples of known catalytic RNA motifs. Importantly, entirely novel ribozyme classes were also discovered, for most of which both structural and biochemical information became rapidly available. However, for the majority of the new ribozymes, which are found in the genomes of a variety of species, a biological function remains elusive. Here, we concentrate on the different approaches to find catalytic RNA motifs in sequence databases. We summarize the emerging principles of RNA catalysis as observed for small endonucleolytic ribozymes. Finally, we address the biological functions of those ribozymes, where relevant information is available and common themes on their cellular activities are emerging. We conclude by speculating on the possibility that the identification and characterization of proteins that we hypothesize to be endogenously associated with catalytic RNA might help in answering the ever-present question of the biological function of the growing number of genomically encoded, small endonucleolytic ribozymes.
Transcriptional signatures of Mycobacterium tuberculosis in mouse model of intraocular tuberculosis.

BACKGROUND Studies on human intraocular tuberculosis (IOTB) are extremely challenging. For understanding the pathogenesis of IOTB, it is important to investigate the mycobacterial transcriptional changes in ocular environment. METHODS Mice were challenged intravenously with M. tuberculosis H37Rv and at 45 days post-infection, experimental IOTB was confirmed based on bacteriological and molecular assays. M. tuberculosis transcriptome was analyzed in the infected eyes using microarray technology. The identified M. tuberculosis signature genes were further validated and investigated in human IOTB samples using real-time polymerase chain reaction. RESULTS Following intravenous challenge with M. tuberculosis, 45% (5/12) mice showed bacilli in the eyes with positivity for M. tuberculosis RNA in 100% (12/12), thus confirming the paucibacillary nature of IOTB similar to human IOTB. M. tuberculosis transcriptome in these infected eyes showed significant upregulation of 12 M. tuberculosis genes and five of these transcripts (Rv0962c, Rv0984, Rv2612c, Rv0974c and Rv0971c) were also identified in human clinically confirmed cases of IOTB. CONCLUSIONS Differentially expressed mycobacterial genes identified in an intravenously challenged paucibacillary mouse IOTB model and presence of these transcripts in human IOTB samples highlights the possible role of these genes for survival of M. tuberculosis in the ocular environment thus contributing to pathogenesis of IOTB.
Broad regulation of gene isoform expression by Wnt signaling in cancer

Differential gene isoform expression is a ubiquitous mechanism to enhance proteome diversity and maintain cell homeostasis. Mechanisms such as splicing that drive gene isoform variability are highly dynamic and responsive to changes in cell signaling pathways. Wnt/β-catenin signaling has profound effects on cell activity and cell fate and is known to modify several splicing events by altering the expression of individual splicing factors. However, a global assessment of how extensively Wnt signaling regulates splicing and other mechanisms that determine mRNA isoform composition in cancer is lacking. We used deep time-resolved RNA-seq in two independent in vivo Wnt-addicted tumor models during treatment with the potent Wnt inhibitor ETC-159 and examined Wnt regulated splicing events and splicing regulators. We found 1025 genes that underwent Wnt regulated variable exon usage leading to isoform expression changes. This was accompanied by extensive Wnt regulated changes in the expression of splicing regulators. Many of these Wnt regulated events were conserved in multiple human cancers, and many were linked to previously defined cancer-associated splicing quantitative trait loci. This suggests that the Wnt regulated splicing events are components of fundamental oncogenic processes. These findings demonstrate the wide-ranging effects of Wnt signaling on the isoform composition of the cell and provides an extensive resource of expression changes of splicing regulators and gene isoforms regulated by Wnt signaling.
Total energy expenditure measured using doubly labeled water compared with estimated energy requirements in older adults (≥65 y): analysis of primary data

ABSTRACT Background Contemporary energy expenditure data are crucial to inform and guide nutrition policy in older adults to optimize nutrition and health. Objective The aim was to determine the optimal method of estimating total energy expenditure (TEE) in adults (aged ≥65 y) through 1) establishing which published predictive equations have the closest agreement between measured resting metabolic rate (RMR) and predicted RMR and 2) utilizing the RMR equations with the best agreement to predict TEE against the reference method of doubly labeled water (DLW). Methods A database consisting of international participant-level TEE data from DLW studies was developed to enable comparison with energy requirements estimated by 17 commonly used predictive equations. This database included 31 studies comprising 988 participant-level RMR data and 1488 participant-level TEE data. Mean physical activity level (PAL) was determined for men (PAL = 1.69, n = 320) and women (PAL = 1.66, n = 668). Bland–Altman plots assessed agreement of measured RMR and TEE with predicted RMR and TEE in adults aged ≥65 y, and subgroups of 65–79 y and ≥80 y. Linear regression assessed proportional bias. Results The Ikeda, Livingston, and Mifflin equations most closely agreed with measured RMR and TEE in all adults aged ≥65 y and in the 65–79 y and ≥80 y subgroups. In adults aged ≥65 y, the Ikeda and Livingston equations overestimated TEE by a mean ± SD of 175 ± 1362 kJ/d and 86 ± 1344 kJ/d, respectively. The Mifflin equation underestimated TEE by a mean ± SD of 24 ± 1401 kJ/d. Proportional bias was present as energy expenditure increased. Conclusions The Ikeda, Livingston, or Mifflin equations are recommended for estimating energy requirements of older adults. Future research should focus on developing predictive equations to meet the requirements of the older population with consideration given to body composition and functional measures.
Mating system variation in hybrid zones: facilitation, barriers and asymmetries to gene flow

Summary Plant mating systems play a key role in structuring genetic variation both within and between species. In hybrid zones, the outcomes and dynamics of hybridization are usually interpreted as the balance between gene flow and selection against hybrids. Yet, mating systems can introduce selective forces that alter these expectations; with diverse outcomes for the level and direction of gene flow depending on variation in outcrossing and whether the mating systems of the species pair are the same or divergent. We present a survey of hybridization in 133 species pairs from 41 plant families and examine how patterns of hybridization vary with mating system. We examine if hybrid zone mode, level of gene flow, asymmetries in gene flow and the frequency of reproductive isolating barriers vary in relation to mating system/s of the species pair. We combine these results with a simulation model and examples from the literature to address two general themes: (1) the two‐way interaction between introgression and the evolution of reproductive systems, and (2) how mating system can facilitate or restrict interspecific gene flow. We conclude that examining mating system with hybridization provides unique opportunities to understand divergence and the processes underlying reproductive isolation.
Heuristic Approaches for Enhancing the Privacy of the Leader in IoT Networks

The privacy and security of the Internet of Things (IoT) are emerging as popular issues in the IoT. At present, there exist several pieces of research on network analysis on the IoT network, and malicious network analysis may threaten the privacy and security of the leader in the IoT networks. With this in mind, we focus on how to avoid malicious network analysis by modifying the topology of the IoT network and we choose closeness centrality as the network analysis tool. This paper makes three key contributions toward this problem: (1) An optimization problem of removing k edges to minimize (maximize) the closeness value (rank) of the leader; (2) A greedy (greedy and simulated annealing) algorithm to solve the closeness value (rank) case of the proposed optimization problem in polynomial time; and (3)UpdateCloseness (FastTopRank)—algorithm for computing closeness value (rank) efficiently. Experimental results prove the efficiency of our pruning algorithms and show that our heuristic algorithms can obtain accurate solutions compared with the optimal solution (the approximation ratio in the worst case is 0.85) and outperform the solutions obtained by other baseline algorithms (e.g., choose k edges with the highest degree sum).
Structural basis for power stroke vs. Brownian ratchet mechanisms of motor proteins

Two mechanisms have been proposed for the function of motor proteins: The power stroke and the Brownian ratchet. The former refers to generation of a large downhill free energy gradient over which the motor protein moves nearly irreversibly in making a step, whereas the latter refers to biasing or rectifying the diffusive motion of the motor. Both mechanisms require input of free energy, which generally involves the processing of an ATP (adenosine 5′-triphosphate) molecule. Recent advances in experiments that reveal the details of the stepping motion of motor proteins, together with computer simulations of atomistic structures, have provided greater insights into the mechanisms. Here, we compare the various models of the power stroke and the Brownian ratchet that have been proposed. The 2 mechanisms are not mutually exclusive, and various motor proteins employ them to different extents to perform their biological function. As examples, we discuss linear motor proteins Kinesin-1 and myosin-V, and the rotary motor F1-ATPase, all of which involve a power stroke as the essential element of their stepping mechanism.
Estimation of Source-Specific Occupational Benzene Exposure in a Population-Based Case-Control Study of Non-Hodgkin Lymphoma.

OBJECTIVES Occupational exposures in population-based case-control studies are increasingly being assessed using decision rules that link participants' responses to occupational questionnaires to exposure estimates. We used a hierarchical process that incorporated decision rules and job-by-job expert review to assign occupational benzene exposure estimates in a US population-based case-control study of non-Hodgkin lymphoma. METHODS We conducted a literature review to identify scenarios in which occupational benzene exposure has occurred, which we grouped into 12 categories of benzene exposure sources. For each source category, we then developed decision rules for assessing probability (ordinal scale based on the likelihood of exposure > 0.02 ppm), frequency (proportion of work time exposed), and intensity of exposure (in ppm). The rules used the participants' occupational history responses and, for a subset of jobs, responses to job- and industry-specific modules. For probability and frequency, we used a hierarchical assignment procedure that prioritized subject-specific module information when available. Next, we derived job-group medians from the module responses to assign estimates to jobs with only occupational history responses. Last, we used job-by-job expert review to assign estimates when job-group medians were not available or when the decision rules identified possible heterogeneous or rare exposure scenarios. For intensity, we developed separate estimates for each benzene source category that were based on published measurement data whenever possible. Frequency and intensity annual source-specific estimates were assigned only for those jobs assigned ≥75% probability of exposure. Annual source-specific concentrations (intensity × frequency) were summed to obtain a total annual benzene concentration for each job. RESULTS Of the 8827 jobs reported by participants, 8% required expert review for one or more source categories. Overall, 287 (3.3%) jobs were assigned ≥75% probability of exposure from any benzene source category. The source categories most commonly assigned ≥75% probability of exposure were gasoline and degreasing. The median total annual benzene concentration among jobs assigned ≥75% probability was 0.11 ppm (interquartile range: 0.06-0.55). The highest source-specific median annual concentrations were observed for ink and printing (2.3 and 1.2 ppm, respectively). CONCLUSIONS The applied framework captures some subject-specific variability in work tasks, provides transparency to the exposure decision process, and facilitates future sensitivity analyses. The developed decision rules can be used as a starting point by other researchers to assess occupational benzene exposure in future population-based studies.
Extended spectrum beta‐lactamase producing Shiga‐toxin producing‐Escherichia coli in piglets, humans and water sources in North East region of India

Extended spectrum β‐lactamases (ESBL) producing Shiga toxin producing E. coli (STEC) are posing a constant threat to public health throughout the world leading to serious infections and raising key therapeutic issues. A total of 219 fecal samples were collected from piglets with diarrheoa, pig farmers and water sources in North East India; and were processed for isolation of Escherichia coli. The isolates were screened for antimicrobial resistance and suspected isolates for ESBLs production by double‐disk synergy test (DDST). Escherichia coli isolates positive for DDST were subjected for detection of selected ESBL/beta‐lactamase genes and virulence associated genes by PCR. By DDST, 337 (67·94%) E. coli isolates were detected as ESBLs producer, of which 211 (66·98%), 117 (70·91%) and 9 (56·25%) isolates were from piglets, humans and water sources respectively. A total of 64 (12·90%) isolates were recorded as STEC, of which 48 (9·68%), 6 (1·21%) and 10 (2·02%) were from human, piglets and water respectively. Majority of the STEC isolates (64·06%) possessed multiple virulence genes, of which 59·38% also harboured ESBL/beta‐lactamase genes with 32·81% STEC isolates being positive for multiple ESBL/beta‐lactamase genes.
Urine Haptoglobin/Creatinine Ratio Correlates with Tubular Injury Biomarkers and Severity of Albuminuria in Type 2 Diabetes Patients

Abstract This aim of this study was to investigate the correlation between urine haptoglobin/creatinine ratio(UHCR) and tubular injury biomarkers or severity of albuminuria in type 2 diabetes. Recruited T2DM patients (n=120) were divided into three groups based on urine albumin/creatinine ratio (UACR): normal albuminuria (Normo group, UACR<30 mg/g, n=40), microalbuminuria (Micro group, 30 mg/g ≤UACR<300 mg/g, n=38), and macroalbuminuria (Macro group, UACR ≥300 mg/g, n=42), with matched healthy individuals (NC group, n=30) as controls. ELISA assay was used to detect the levels of urine haptoglobin, NGAL and KIM-1. Automated biochemical analyzer was applied to detect the concentrations of urine creatinine and retinol binding protein (RBP). To eliminate concentration errors, urine NGAL, KIM-1, and RBP were normalized by creatinine and expressed as UHCR, UNCR, UKCR, and URCR, respectively. We found UHCR was significantly increased in T2DM patients as compared with NC group. Among the three diabetic groups, the Macro group had the highest level of UHCR, whereas the Normo group had the lowest level. T2DM patients with higher UHCR levels also had higher levels of UNCR, UKCR, and URCR. Spearman’s correlation analysis indicated that UHCR was positively correlated with UACR, UNCR, UKCR, or URCR levels, and negatively correlated with eGFR. ROC curve analysis showed that UHCR was a sensitive and specific indicator for early diagnosis of DN. Stepwise multiple regression analysis showed that UHCR and UNCR were independent variables for UACR. Our research demonstrated that UHCR correlates with tubular injury biomarkers, including UNCR, UKCR, and URCR, and is independently associated with the severity of albuminuria in T2DM.
miR-378a influences vascularization in skeletal muscles.

AIMS MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumor angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischemic injury in mice. METHODS AND RESULTS Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischemic muscles in both normo- and hyperglycemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibers was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischemic skeletal muscles of miR-378+/+ mice already on day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors (AAV)-based miR-378a overexpression was enough to improve the revascularization of the ischemic limb of wild type mice on day 7 after FAL, what was not reported after systemic delivery of vectors.In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS Data indicates miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation. A TRANSLATIONAL PERSPECTIVE The study reports elevated expression of miR-378a-3p in the plasma of mice subjected to femoral artery ligation and in the plasma of patients with intermittent claudication. Thus, miR-378a may be considered as a marker of ischemic muscle injury.
Keep calm and carry on: electrophysiological evaluation of emotional anticipation in the second language

Abstract Investigations of the so-called ‘foreign language effect’ have shown that emotional experience is language-dependent in bilingual individuals. Response to negative experiences, in particular, appears attenuated in the second language (L2). However, the human brain is not only reactive, but it also builds on past experiences to anticipate future events. Here, we investigated affective anticipation in immersed Polish–English bilinguals using a priming paradigm in which a verbal cue of controlled affective valence allowed making predictions about a subsequent picture target. As expected, native word cues with a negative valence increased the amplitude of the stimulus preceding negativity, an electrophysiological marker of affective anticipation, as compared with neutral ones. This effect was observed in Polish–English bilinguals and English monolinguals alike. The contrast was non-significant when Polish participants were tested in English, suggesting a possible reduction in affective sensitivity in L2. However, this reduction was not validated by a critical language × valence interaction in the bilingual group, possibly because they were highly fluent in English and because the affective stimuli used in the present study were particularly mild. These results, which are neither fully consistent nor inconsistent with the foreign language effect, provide initial insights into the electrophysiology of affective anticipation in bilingualism.
Gender Discrepancies Related to Pediatrician Work-Life Balance and Household Responsibilities

In this study, we examine experiences and satisfaction of pediatricians with their household responsibilities and work-life balance and how these experiences differ by gender. BrightcoveDefaultPlayer10.1542/6063116061001PEDS-VA_2018-2926 Video Abstract BACKGROUND: Physicians must balance career and home responsibilities, yet previous studies on work-life balance are focused primarily on work-based tasks. We examined gender discrepancies and factors related to household responsibilities and work-life balance among pediatricians. METHODS: We used 2015 data from the American Academy of Pediatrics Pediatrician Life and Career Experience Study, a longitudinal study of early-career pediatricians. χ2 tests and multivariable logistic regression were used to examine the effects of gender on household responsibilities, satisfaction, and work-life balance attainment. We formally reviewed responses from 2 open-ended questions on work-life balance challenges and strategies for common themes. RESULTS: Seventy-two percent of participants completed the survey (1293 of 1801). Women were more likely than men to report having primary responsibility for 13 of 16 household responsibilities, such as cleaning, cooking, and routine care of children (all P < .001). All gender differences except budget management remained significant when controlling for part-time work status and spouse or partner work status (P < .05). Women were less satisfied with their share of responsibilities relative to others (52% vs 62%; P < .001), and few women and men report being very successful at achieving balance between their job and other life areas (15% vs 19%, respectively; P = .05). Open-ended responses (n = 1145) revealed many barriers to achieving work-life balance. Strategies to increase work-life balance included reducing work hours, outsourcing household-related work, and adjustments to personal responsibilities and relationships. CONCLUSIONS: Female pediatricians spend more time on household responsibilities than male pediatricians, and gender is a key factor associated with work-life balance satisfaction.