Miracle-dz/UniFAR-FTUs huggingface dataset:
Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification

Significance Persistent infection by the high-risk human papillomaviruses (HPVs) can lead to anogenital and head and neck cancers. The HPV vaccines effectively prevent new type-restricted infections but have no effect on preexisting infections. It is crucial to identify effective inhibitors of preneoplastic HPV infections. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and are also essential for chromatin replication fork progression. Here we show that Vorinostat, a pan-HDAC inhibitor, stabilizes host cell tumor suppressors targeted by HPV oncoproteins E6 and E7 and abrogates productive infection by a high-risk HPV in organotypic cultures of human keratinocytes. Furthermore, Vorinostat selectively induces apoptosis in HPV-infected cells by decreasing DNA repair response while increasing the proapoptotic protein Bim. Vorinostat appears to be a promising therapeutic agent. Human papillomaviruses (HPVs) cause epithelial proliferative diseases. Persistent infection of the mucosal epithelia by the high-risk genotypes can progress to high-grade dysplasia and cancers. Viral transcription and protein activities are intimately linked to regulation by histone acetyltransferases and histone deacetylases (HDACs) that remodel chromatin and regulate gene expression. HDACs are also essential to remodel and repair replicating chromatin to enable the progression of replication forks. As such, Vorinostat (suberoylanilide hydroximic acid), and other pan-HDAC inhibitors, are used to treat lymphomas. Here, we investigated the effects of Vorinostat on productive infection of the high-risk HPV-18 in organotypic cultures of primary human keratinocytes. HPV DNA amplifies in the postmitotic, differentiated cells of squamous epithelia, in which the viral oncoproteins E7 and E6 establish a permissive milieu by destabilizing major tumor suppressors, the pRB family proteins and p53, respectively. We showed that Vorinostat significantly reduced these E6 and E7 activities, abrogated viral DNA amplification, and inhibited host DNA replication. The E7-induced DNA damage response, which is critical for both events, was also compromised. Consequently, Vorinostat exposure led to DNA damage and triggered apoptosis in HPV-infected, differentiated cells, whereas uninfected tissues were spared. Apoptosis was attributed to highly elevated proapoptotic Bim isoforms that are known to be repressed by EZH2 in a repressor complex containing HDACs. Two other HDAC inhibitors, Belinostat and Panobinostat, also inhibited viral DNA amplification and cause apoptosis. We suggest that HDAC inhibitors are promising therapeutic agents to treat benign HPV infections, abrogate progeny virus production, and hence interrupt transmission.
Fasiglifam-Induced Liver Injury in Patients With Type 2 Diabetes: Results of a Randomized Controlled Cardiovascular Outcomes Safety Trial

OBJECTIVE To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein–coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3–5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ≥10 × ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration–mandated CV outcomes trial supported the termination of the fasiglifam clinical program.
Wavelet-Based Correlation Identification of Scales and Locations between Landscape Patterns and Topography in Urban-Rural Profiles: Case of the Jilin City, China

Landscapes display overlapping sets of correlations in different regions at different spatial scales, and these correlations can be delineated by pattern analysis. This study identified the correlations between landscape pattern and topography at various scales and locations in urban-rural profiles from Jilin City, China, using Pearson correlation analysis and wavelet method. Two profiles, 30 km (A) and 35 km (B) in length with 0.1-km sampling intervals, were selected. The results indicated that profile A was more sensitive to the characterization of the land use pattern as influenced by topography due to its more varied terrain, and three scales (small, medium, and large) could be defined based on the variation in the standard deviation of the wavelet coherency in profile A. Correlations between landscape metrics and elevation were similar at large scales (over 8 km), while complex correlations were discovered at other scale intervals. The medium scale of cohesion and Shannon’s diversity index was 1–8 km, while those of perimeter-area fractal dimension and edge density index were 1.5–8 km and 2–8 km, respectively. At small scales, the correlations were weak as a whole and scattered due to the micro-topography and landform elements, such as valleys and hillsides. At medium scales, the correlations were most affected by local topography, and the land use pattern was significantly correlated with topography at several locations. At large spatial scales, significant correlation existed throughout the study area due to alternating mountains and plains. In general, the strength of correlation between landscape metrics and topography increased gradually with increasing spatial scale, although this tendency had some fluctuations in several locations. Despite a complex calculating process and ecological interpretation, the wavelet method is still an effective tool to identify multi-scale characteristics in landscape ecology.
Current considerations in AYA Hodgkin lymphoma

Hodgkin lymphoma (HL) commonly occurs in adolescents and young adults (AYA), defined by the National Cancer Institute as people diagnosed with cancer between the ages of 15 and 39 years. Despite therapeutic advances, the AYA population has derived less incremental benefit compared to both paediatric and adult counterparts. Although the exact aetiology is unclear, contributing factors probably include differences in disease biology, delayed diagnosis, decreased participation in clinical trials and treatment adherence secondary to complex social factors. As such, while HL remains highly curable, there is not a clear consensus regarding the management of patients within this age range, specifically whether paediatric or adult regimens are preferred or how best to incorporate emerging therapeutic advancements. Ongoing clinical trials, as well as continued collaborative efforts are required to address the needs of this population, investigate the potential for unique biological factors and allow for optimization of treatment. Here we review current prognostic and treatment strategies for paediatric and adult patients with HL and highlight complexities around the management of this patient population.
Self-Reported Fatigue in Children Following Intensive Care Treatment*

Objectives: Adults report high levels of fatigue after intensive care, but little is known about pediatric survivors. This study aimed to explore rates of self-reported fatigue in children after critical illness. Design: Prospective cohort study. Setting: Tertiary children’s hospital. Patients: Ninety-seven children aged 7–17 years old. Interventions: None. Measurements and Main Results: Children completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale 3 months after discharge from PICU. Comparisons with normative data (n = 209) showed that PICU survivors reported similar mean (SD) total fatigue scores to their healthy peers (79.6 [16.3] vs 81.8 [12.5]; p = 0.239), but greater cognitive fatigue (77.4 [21.9] vs 82.4 [16.4]; p = 0.048). Also children who had sustained a traumatic brain injury reported “less” sleep/rest fatigue (84.6 [15.0] vs 76.8 [16.3]; p = 0.006). Baseline indices of severity of illness were not associated with fatigue. Conclusions: The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale appears to be a promising tool for use in outcomes research with PICU survivors. These results highlight the need to bear in mind the heterogeneity of PICU patients and the multidimensional nature of fatigue symptoms.
Diagnostic Performance of Plain Film, Ultrasonography, and Computed Tomography in Nasal Bone Fractures: A Systematic Review

Purpose: The aim of this study was to compare the diagnostic performance (accuracy, sensitivity, specificity, positive predictive value, and negative predictive value) of plain film (PF), ultrasonography (USG), and computed tomography (CT) in diagnosing nasal bone fractures (NBFs). Methods: In a search of PubMed and Scopus, “nasal bone fracture” AND “X-ray OR CT OR USG OR MRI” were searched. Among the 369 titles from PubMed and 379 titles from Scopus, 257 duplicate titles were excluded and 491 titles were reviewed. Among them, 36 full articles were reviewed. From these, 21 were excluded and 1 mined article was added; thus, 16 articles were reviewed. Results: The accuracy of CT (94.4% ± 2.3%) was significantly higher (P < .001) than that of USG (85.0% ± 3.6%). The accuracy of USG was significantly higher (P < .001) than that of PF (67.7% ± 4.7%). Computed tomography (89.3% ± 3.1%) and USG (87.2% ± 3.3%) were significantly more sensitive than PF (P < .001 and P < .001, respectively). The specificity of CT (94.2% ± 2.3%) was significantly higher (P = .001) than that of USG (87.4% ± 3.3%). The specificity of USG was significantly higher (P < .001) than that of PF (67.8% ± 4.7%). Among the PF techniques, combining a lateral view and the Water’s view (71.8% ± 4.5%) had significantly higher accuracy than a lateral view alone (62.4% ± 4.8%) or the Water’s view alone (61.0% ± 4.9%). In USG, there was no significant difference (P = .300) in accuracy among lateral and dorsal views (95.8% ± 2.0%), a lateral view alone (84.2% ± 3.7%), and a dorsal view alone (84.2% ± 3.6%). Conclusion: The results of this review might be helpful in choosing the most appropriate diagnostic tool in patients suspected having NBF.
Elevated pCO2 alters marine heterotrophic bacterial community composition and metabolic potential in response to a pulse of phytoplankton organic matter

Factors that affect the respiration of organic carbon by marine bacteria can alter the extent to which the oceans act as a sink of atmospheric carbon dioxide. We designed seawater dilution experiments to assess the effect of pCO2 enrichment on heterotrophic bacterial community composition and metabolic potential in response to a pulse of phytoplankton-derived organic carbon. Experiments included treatments of elevated (1000 p.p.m.) and low (250 p.p.m.) pCO2 amended with 10 μmol L-1 dissolved organic carbon from Emiliana huxleyi lysates, and were conducted using surface-seawater collected from the South Pacific Subtropical Gyre. To assess differences in community composition and metabolic potential, shotgun metagenomic libraries were sequenced from low and elevated pCO2 treatments collected at the start of the experiment and following exponential growth. Our results indicate bacterial communities changed markedly in response to the organic matter pulse over time and were significantly affected by pCO2 enrichment. Elevated pCO2 also had disproportionate effects on the abundance of sequences related to proton pumps, carbohydrate metabolism, modifications of the phospholipid bilayer, resistance to toxic compounds and conjugative transfer. These results contribute to a growing understanding of the effects of elevated pCO2 on bacteria-mediated carbon cycling during phytoplankton bloom conditions in the marine environment.
Change classification and its applications to program development and testing

During program development, testing and code editing are inter-leaved activities. When tests unexpectedly fail, the changes that caused the failure are not always easy to ﬁnd. We present several analyses that automatically classify changes as Red , Yellow , or Green , indicating the likelihood that they contributed to a test’s failure. We implemented these techniques as an extension of the JUnit testing framework, and evaluated their effectiveness in two case studies. Our results indicate that change classiﬁcation can effectively focus programmer attention on failure-inducing changes, improving on current manual searching/debugging techniques. Change classiﬁcation can also determine untested changes, to inform programmers that additional tests are needed. Furthermore, change classiﬁcation can determine those changes that can be committed safely to a version control repository without breaking any tests, even if a developer’s local workspace contains failing tests. Early adoption of edited code avoids inefﬁcient parallel implementations of the same functionality and possible conﬂicts when merging independent changes later in the development process.
Quality and Readability of English-Language Internet Information for Tinnitus

Abstract Background: Because of the wealth of information available on the internet and increasing numbers of individuals relying on websites as a primary source of information for health-related questions, it is important that the readability of their content is within the comprehension level of most readers. Objective: The study evaluated the quality and readability of English-language Internet information for tinnitus. Research Design: Analysis of Internet websites on tinnitus. Study Sample: A total of 134 websites with tinnitus information. Data Collection and Analysis: Three key words (i.e., tinnitus, ringing in the ear, and buzzing in the ear) were entered in five country-specific versions of the most commonly used internet search engine in August 2016. For each of the 15 searches, the first 20 relevant websites were examined. After removing duplicates, a total of 134 websites were assessed. Their origin (commercial, nonprofit organization, government, personal, or university), quality (Health On the Net [HON] certification and DISCERN scores), and readability (Flesch Reading Ease score, Flesch-Kincaid Reading Grade Level Formula, and Simple Measure of Gobbledygook) were assessed. Results: Most websites were of commercial (49.3%) or nonprofit organization (38.8%) origin. Their quality and readability was highly variable. Only 13.5% of websites had HON certification. χ2 analysis showed that there was significant association between website origin and HON certification [χ2(4) = 132.9, p < 0.0001]. The mean DISCERN scores were 2.39. No association between DISCERN scores and website origin was found. Readability measures showed that on average, only people with at least 10–12 yr of education could read and understand the internet information for tinnitus in websites. Almost all the websites exceeded the most stringent reading level recommended for health information. Conclusions: The results highlight great variability in the quality and readability of health information, specifically for tinnitus in the internet. These findings underscores the need for stakeholders (e.g., web-developers, clinicians) to be aware of this and to develop more user-friendly health information on websites to make it more accessible for people with low literacy.
Occurrence of Hippocampal Ripples is Associated with Activity Suppression in the Mediodorsal Thalamic Nucleus

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal–prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal–cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01–0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal–cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non–rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal–cortical networks supporting “on-line” and “off-line” information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments. SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal–prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in “off-line” consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer.
Performance of Frontline Demonstration on Yield Enhancement of Cumin in Barmer District of Rajasthan

The present study was conducted in Barmer district of Rajasthan. The front line demonstrations on cumin crop conducted by Krishi Vigyan Kendra, Danta, Barmer during the last three years (2013-14 to 201516). The results showed 31.90 to 62.19 per cent yield increase in FLDs over farmers practice during 2013-14 to 2015-2016. The extension gap, technology gap and technology index were 2.67 q/ha, 2.50 q/ha and 29.41 per cent, respectively. Therefore, front line demonstration programme was an effective tool for increasing the productivity of cumin and changing knowledge, attitude and skill of farmers. This created greater awareness and motivated the other farmers to adopt improved practices of Cumin.
The Enhanced Catalytic Performance and Stability of Ordered Mesoporous Carbon Supported Nano-gold with High Structural Integrity for Glycerol Oxidation.

Ordered mesoporous carbon (OMC) supported gold nanoparticles of size 3-4 nm having uniform dispersion were synthesized by sol-immobilization method. OMCs such as CMK-3 and NCCR-56 with high surface area and uniform pore size were obtained, respectively, using ordered mesoporous silicas such as SBA-15 and IITM-56 as hard templates, respectively. The resulting OMC supported monodispersed nano-gold, i. e. , Au/CMK-3 and Au/NCCR-56, exhibited excellent performance as mild-oxidizing catalysts for oxidation of glycerol with high hydrothermal stability. Further, unlike activated carbon supported nano-gold catalysts (Au/AC), the OMC supported nano-gold catalysts, i. e. , Au/CMK-3 and Au/NCCR-56, show no aggregation of active species even after recycling. Thus, in the case of Au/CMK-3 and Au/NCCR-56, both the fresh and regenerated catalysts showed excellent performane for the chosen reaction owing to an enhanced textural integrity of the catalysts and that with remarkable selectivity towards glyceric acid. The significance of the OMC supports in maintaining the dispersion of gold nanoparticles is explicit from this study, and that the activity of Au/AC catalyst is considerably decreased (∼50 %) upon recycling as a result of agglomeration of the active gold nanoparticles over the disordered amorphous carbon matrix.
Healthy volunteers' perceptions of risk in US Phase I clinical trials: A mixed-methods study

Background There is limited research on healthy volunteers’ perceptions of the risks of Phase I clinical trials. In order to contribute empirically to long-standing ethical concerns about healthy volunteers’ involvement in drug development, it is crucial to assess how these participants understand trial risks. The objectives of this study were to investigate (1) participants’ views of the overall risks of Phase I trials, (2) their views of the risk of personally being harmed in a trial, and (3) how risk perceptions vary across participants’ clinical trial history and sociodemographic characteristics. Methods and findings We qualitatively and quantitatively analyzed semi-structured interviews conducted with 178 healthy volunteers who had participated in a diverse range of Phase I trials in the United States. Participants had collective experience in a reported 1,948 Phase I trials (mean = 10.9; median = 5), and they were interviewed as part of a longitudinal study of healthy volunteers’ risk perceptions, their trial enrollment decisions, and their routine health behaviors. Participants’ qualitative responses were coded, analyzed, and subsequently quantified in order to assess correlations between their risk perceptions and demographics, such as their race/ethnicity, gender, age, educational attainment, employment status, and household income. We found that healthy volunteers often viewed the overall risks of Phase I trials differently than their own personal risk of harm. The majority of our participants thought that Phase I trials were medium, high, or extremely high risk (118 of 178), but most nonetheless felt that they were personally safe from harm (97 of 178). We also found that healthy volunteers in their first year of clinical trial participation, racial and ethnic minority participants, and Hispanic participants tended to view the overall trial risks as high (respectively, Jonckheere-Terpstra, −2.433, p = 0.015; Fisher exact test, p = 0.016; Fisher exact test, p = 0.008), but these groups did not differ in regard to their perceptions of personal risk of harm (respectively, chi-squared, 3.578, p = 0.059; chi-squared, 0.845, p = 0.358; chi-squared, 1.667, p = 0.197). The main limitation of our study comes from quantitatively aggregating data from in-depth interviews, which required the research team to interpret participants’ nonstandardized risk narratives. Conclusions Our study demonstrates that healthy volunteers are generally aware of and reflective about Phase I trial risks. The discrepancy in healthy volunteers’ views of overall and personal risk sheds light on why healthy volunteers might continue to enroll in clinical trials, even when they view trials on the whole as risky.