Miracle-dz/UniFAR-FTUs huggingface dataset:
Estrous cycle impacts microRNA content in extracellular vesicles that modulate bovine cumulus cell transcripts during in vitro maturation†

Abstract Extracellular vesicles (EVs) are nanoparticles secreted by ovarian follicle cells. Extracellular vesicles are an important form of intercellular communication, since they carry bioactive contents, such as microRNAs (miRNAs), mRNAs, and proteins. MicroRNAs are small noncoding RNA capable of modulating mRNA translation. Thus, EVs can play a role in follicle and oocyte development. However, it is not clear if EV contents vary with the estrous cycle stage. The aim of this study was to investigate the bovine miRNA content in EVs obtained from follicles at different estrous cycle stages, which are associated with different progesterone (P4) levels in the follicular fluid (FF). We collected FF from 3 to 6 mm follicles and evaluated the miRNA profile of the EVs and their effects on cumulus-oocyte complexes during in vitro maturation. We observed that EVs from low P4 group have a higher abundance of miRNAs predicted to modulate pathways, such as MAPK, RNA transport, Hippo, Cell cycle, FoxO, oocyte meiosis, and TGF-beta. Additionally, EVs were taken up by cumulus cells and, thus, affected the RNA global profile 9 h after EV supplementation. Cumulus cells supplemented with EVs from low P4 presented upregulated genes that could modulate biological processes, such as oocyte development, immune responses, and Notch signaling compared with genes of cumulus cells in the EV free media or with EVs from high P4 follicles. In conclusion, our results demonstrate that EV miRNA contents are distinct in follicles exposed to different estrous cycle stage. Supplementation with EVs impacts gene expression and biological processes in cumulus cells. Summary Sentence MicroRNA contents of small EVs obtained from bovine follicular fluid are modified depending on the estrous cycle stage and can modulate the RNA profile of cumulus cells during in vitro oocyte maturation.
Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial‐to‐mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E‐cadherin‐ and nuclear ZEB1‐positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient‐derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient‐matched liver metastases presumably developing through mesenchymal‐to‐epithelial transition. Inhibition of E‐cadherin or ZEB1 expression by shRNA notably prevented the PDX‐derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E‐cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.
11C‐PK11195 PET imaging and white matter changes in Parkinson’s disease dementia

There is evidence of increased microglial activation in Parkinson’s disease (PD) as shown by in vivo PET ligand such as 11C‐PK11195. In addition, diffusion tensor imaging (DTI) imaging reveals widespread changes in PD, especially when the associated dementia develops. In the present case series, we studied five subjects with Parkinson’s disease dementia (PDD). Our findings suggest that while DTI metrics mirror cognitive severity, higher 11C‐PK11195 binding seems to be associated with a relative preservation of both white matter tracts and cognition. Longitudinal studies are warranted to tackle the complex relationship between microglial activation and structural abnormalities in neurodegenerative conditions.
Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial.

AIMS Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease. METHODS AND RESULTS Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months). CONCLUSION There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.
Evolution & Development

Funding information National Science Foundation; National Aeronautics and Space Administration; John Simon Guggenheim Foundation Abstract A fuller understanding of the role of developmental bias in shaping large‐scale evolutionary patterns requires integrating bias (the probability distribution of variation accessible to an ancestral phenotype) with clade dynamics (the differential survival and production of species and evolutionary lineages). This synthesis could proceed as a two‐way exchange between the developmental data available to neontologists and the strictly phenotypic but richly historical and dynamic data available to paleontologists. Analyses starting in extant populations could aim to predict macroevolution in the fossil record from observed developmental bias, while analyses starting in the fossil record, particularly the record of extant species and lineages, could aim to predict developmental bias from macroevolutionary patterns, including the broad range of extinct phenotypes. Analyses in multivariate morphospaces are especially effective when coupled with phylogeny, theoretical and developmental models, and diversity–disparity plots. This research program will also require assessing the “heritability” of an ancestral bias across phylogeny, and the tendency for bias change in strength and orientation over evolutionary time. Such analyses will help find a set of general rules for the macroevolutionary effects of developmental bias, including its impact on and interactions with the other intrinsic and extrinsic factors governing the movement, expansion, and contraction of clades in morphospace.
Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.

AIMS The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. METHODS AND RESULTS Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. CONCLUSION There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT01327846.
2018 Highlights of Urban Entomology

Abstract The field of urban entomology is primarily associated with the study of ants, bed bugs, cockroaches, termites, and other occasional invader pests that are found within or near human-made structures. A wide array of peer-reviewed studies were published in 2018. The topics of these articles ranged from genomes and basic biology of urban insects to various applied aspects of pest management. Key findings of these papers are presented and discussed from the perspective of the contributions they make to the discipline of urban entomology. Additionally, potential future research opportunities that are evident from these publications have been outlined.
Physicians' gender and their use of electronic health records: findings from a mixed-methods usability study

OBJECTIVE Physician burnout associated with EHRs is a major concern in health care. A comprehensive assessment of differences among physicians in the areas of EHR performance, efficiency, and satisfaction has not been conducted. The study sought to study relationships among physicians' performance, efficiency, perceived workload, satisfaction, and usability in using the electronic health record (EHR) with comparisons by age, gender, professional role, and years of experience with the EHR. MATERIALS AND METHODS Mixed-methods assessments of the medical intensivists' EHR use and perceptions. Using simulated cases, we employed standardized scales, performance measures, and extensive interviews. NASA Task Load Index (TLX), System Usability Scale (SUS), and Questionnaire on User Interface Satisfaction surveys were deployed. RESULTS The study enrolled 25 intensive care unit (ICU) physicians (11 residents, 9 fellows, 5 attendings); 12 (48%) were men, with a mean age of 33 (range, 28-55) years and a mean of 4 (interquartile range, 2.0-5.5) years of Epic experience. Overall task performance scores were similar for men (90% ± 9.3%) and women (92% ± 4.4%), with no statistically significant differences (P = .374). However, female physicians demonstrated higher efficiency in completion time (difference = 7.1 minutes; P = .207) and mouse clicks (difference = 54; P = .13). Overall, men reported significantly higher perceived EHR workload stress compared with women (difference = 17.5; P < .001). Men reported significantly higher levels of frustration with the EHR compared with women (difference = 33.15; P < .001). Women reported significantly higher satisfaction with the ease of use of the EHR interface than men (difference = 0.66; P =.03). The women's perceived overall usability of the EHR is marginally higher than that of the men (difference = 10.31; P =.06). CONCLUSIONS Among ICU physicians, we measured significant gender-based differences in perceived EHR workload stress, satisfaction, and usability-corresponding to objective patterns in EHR efficiency. Understanding the reasons for these differences may help reduce burnout and guide improvements to physician performance, efficiency, and satisfaction with EHR use. DESIGN Mixed-methods assessments of the medical intensivists' EHR use and perceptions. Using simulated cases, we employed standardized scales, performance measures, and extensive interviews.
Pediatric Bacterial Meningitis Surveillance in Nigeria From 2010 to 2016, Prior to and During the Phased Introduction of the 10-Valent Pneumococcal Conjugate Vaccine

Abstract Background Historically, Nigeria has experienced large bacterial meningitis outbreaks with high mortality in children. Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Haemophilus influenzae are major causes of this invasive disease. In collaboration with the World Health Organization, we conducted longitudinal surveillance in sentinel hospitals within Nigeria to establish the burden of pediatric bacterial meningitis (PBM). Methods From 2010 to 2016, cerebrospinal fluid was collected from children <5 years of age, admitted to 5 sentinel hospitals in 5 Nigerian states. Microbiological and latex agglutination techniques were performed to detect the presence of pneumococcus, meningococcus, and H. influenzae. Species-specific polymerase chain reaction and serotyping/grouping were conducted to determine specific causative agents of PBM. Results A total of 5134 children with suspected meningitis were enrolled at the participating hospitals; of these 153 (2.9%) were confirmed PBM cases. The mortality rate for those infected was 15.0% (23/153). The dominant pathogen was pneumococcus (46.4%: 71/153) followed by meningococcus (34.6%: 53/153) and H. influenzae (19.0%: 29/153). Nearly half the pneumococcal meningitis cases successfully serotyped (46.4%: 13/28) were caused by serotypes that are included in the 10-valent pneumococcal conjugate vaccine. The most prevalent meningococcal and H. influenzae strains were serogroup W and serotype b, respectively. Conclusions Vaccine-type bacterial meningitis continues to be common among children <5 years in Nigeria. Challenges with vaccine introduction and coverage may explain some of these finding. Continued surveillance is needed to determine the distribution of serotypes/groups of meningeal pathogens across Nigeria and help inform and sustain vaccination policies in the country.
Normal myocardial native T1 values in children using single‐point saturation recovery and modified look–locker inversion recovery (MOLLI)

T1 mapping is useful to quantify diffuse myocardial processes such as fibrosis, edema, storage disorders, or hemochromatosis. Normal pediatric myocardial T1 values are scarce using modified Look–Locker inversion recovery (MOLLI) sequences and unavailable using Smart1Map, a single‐point saturation recovery sequence that measures true T1.
Effect of MyTeen SMS-Based Mobile Intervention for Parents of Adolescents

Key Points Question Is a brief parenting program delivered solely via text message effective in improving parental competence and mental health literacy in parents of adolescents? Findings In this randomized clinical trial of 221 parents and caregivers, significant group differences were observed between those receiving the text-messaging intervention and the control group. Participants who received the text-messaging program reported higher levels of parental competence, improved knowledge of help seeking, improved parent-adolescent communication, and lower levels of parental distress at 1 and 3 months of follow-up compared with the control group. Meaning The text-messaging program appears to be an effective and feasible way to reach and support a large number of parents to improve parental competence and may represent a less expensive option for service delivery.
Systematic minimization of RNA ligase ribozyme through large-scale design-synthesis-sequence cycles

Abstract Template-directed RNA ligation catalyzed by an RNA enzyme (ribozyme) is a plausible and important reaction that could have been involved in transferring genetic information during prebiotic evolution. Laboratory evolution experiments have yielded several classes of ligase ribozymes, but their minimal sequence requirements remain largely unexplored. Because selection experiments strongly favor highly active sequences, less active but smaller catalytic motifs may have been overlooked in these experiments. We used large-scale DNA synthesis and high-throughput ribozyme assay enabled by deep sequencing to systematically minimize a previously laboratory-evolved ligase ribozyme. After designing and evaluating >10 000 sequences, we identified catalytic cores as small as 18 contiguous bases that catalyze template-directed regiospecific RNA ligation. The fact that such a short sequence can catalyze this critical reaction suggests that similarly simple or even simpler motifs may populate the RNA sequence space which could have been accessible to the prebiotic ribozymes.
Cardiotonic steroids as potential Na+/K+-ATPase inhibitors – a computational study

Abstract Cardiotonic steroids (CTS) are steroidal drugs, processed from the seeds and dried leaves of the genus Digitalis as well as from the skin and parotid gland of amphibians. The most commonly known CTS are ouabain, digoxin, digoxigenin and bufalin. CTS can be used for safer medication of congestive heart failure and other related conditions due to promising pharmacological and medicinal properties. Ouabain isolated from plants is widely utilized in in vitro studies to specifically block the sodium potassium (Na+/K+-ATPase) pump. For checking, whether ouabain derivatives are robust inhibitors of Na+/K+-ATPase pump, molecular docking simulation was performed between ouabain and its derivatives using YASARA software. The docking energy falls within the range of 8.470 kcal/mol to 7.234 kcal/mol, in which digoxigenin was found to be the potential ligand with the best docking energy of 8.470 kcal/mol. Furthermore, pharmacophore modeling was applied to decipher the electronic features of CTS. Molecular dynamics simulation was also employed to determine the conformational properties of Na+/K+-ATPase-ouabain and Na+/K+-ATPase-digoxigenin complexes with the plausible structural integrity through conformational ensembles for 100 ns which promoted digoxigenin as the most promising CTS for treating conditions of congestive heart failure patients.
Within- and between-group dynamics in an obligate cooperative breeder.

1Cooperative behaviour can have profound effects on demography. In many cooperative species, components of fitness (e.g. survival, reproductive success) are diminished in smaller social groups. These effects (termed group-level component Allee effects) may lead smaller groups to grow relatively slowly or fail to persist (termed group-level demographic Allee effects). 2If these group-level effects were to propagate to the population level, small populations would grow slowly or decline to extinction (termed population-level demographic Allee effects). However, empirical studies have revealed little evidence of such population-level effects. 3Theoretical studies suggest that dispersal behaviour could either cause or prevent the propagation of group-level Allee effects to the population level. We therefore characterised within-and between-pack dynamics in a population of African wild dogs (Lycaon pictus) to test these contrasting model predictions. 4Larger wild dog packs produced more pups and their members experienced higher survival than those in smaller packs. Nevertheless, larger packs grew more slowly than smaller packs, because natal adults dispersed away from them. Most packs either died out in whole-pack death events, or broke up when their founders died, irrespective of pack size. Overall, packs showed negative density dependence rather than group-level demographic Allee effects. 5Larger packs produced more, but not larger, dispersal groups, and hence generated more, but not larger, new packs. Larger packs thus contributed more than smaller packs to the number of packs in the population, but their large size did not propagate to their daughter packs. This pattern helps to explain the absence of population-level Allee effects in this species. 6Dispersal behaviour, itself driven by natural selection on individual reproductive strategies, played a pivotal role in population dynamics, leading to the formation of new packs and limiting the size of established packs. Understanding dispersal processes is likely to be important to understanding the population dynamics of other cooperatively breeding species.