Miracle-dz/UniFAR-FTUs huggingface dataset:
Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphomas worldwide and is characterized by a high diversity of genetic and molecular alterations. Chromosomal translocations and mutations leading to deregulated expression of the transcriptional repressor BCL6 occur in a significant fraction of DLBCL patients. An oncogenic role of BCL6 in the initiation of DLBCL has been shown as the constitutive expression of BCL6 in mice recapitulates the pathogenesis of human DLBCL. However, the role of BCL6 in tumor maintenance remains poorly investigated due to the absence of suitable genetic models and limitations of pharmacological inhibitors. Here, we have utilized tetracycline-inducible CRISPR/Cas9 mutagenesis to study the consequences of BCL6 deletion in established DLBCL models in culture and in vivo. We show that BCL6 knock-out in SU-DHL-4 cells in vitro results in an anti-proliferative response 4–7 days after Cas9 induction that was characterized by cell cycle (G1) arrest. Conditional BCL6 deletion in established DLBCL tumors in vivo induced a significant tumor growth inhibition with initial tumor stasis followed by slow tumor growth kinetics. Our findings support a role of BCL6 in the maintenance of lymphoma growth and showcase the utility of inducible CRISPR/Cas9 systems for probing oncogene addiction.
Parkinson’s Disease in the Middle East, North Africa, and South Asia: Consensus from the International Parkinson and Movement Disorder Society Task Force for the Middle East

Background: Understanding the regional needs and available healthcare resources to treat Parkinson’s disease (PD) is essential to plan appropriate future priorities. The International Parkinson and Movement Disorder Society (MDS) Task Force for the Middle East was established to raise awareness and promote education across the region on PD and other movement disorders. Broadly, the task force encompasses the countries of the Middle East but has included North Africa and South Asia as well (MENASA). Objective: To create a list of needs and priorities in the advancement of PD in MENASA countries based on consensuses generated by the MDS task force for the Middle East. Methods: A Strengths Weaknesses-Opportunities-Threats (SWOT) analysis was conducted by the task force members to generate consensus about PD care this region. Results: Eight overarching principles emerged for the consensus statement on current needs: more movement disorders specialists, multidisciplinary care, accurate epidemiologic data, educational programs, availability of drugs, and availability of more advanced therapy, enhanced health care resources and infrastructure, and greater levels of awareness within the general population and among health care professionals. Conclusion: This pilot study sheds light on unmet needs for providing care to people with PD in the MENASA region. These data offer directions on priorities to increase awareness of PD, to develop better infrastructure for research and management of PD, to foster healthcare policy discussions for PD and to provide educational opportunities within these countries.
Targeting an interaction between two disordered domains using a designed peptide.

Intrinsically disordered regions in proteins (IDRs) mediate many disease-related protein-protein interactions. However, the unfolded character and continuous conformational changes of IDRs make them difficult to target for therapeutic purposes. Here we show that a designed peptide based on the disordered p53 linker domain can be used for targeting a partner IDR from the anti-apoptotic iASPP protein, promoting apoptosis of cancer cells. The p53 linker forms a hairpin-like structure with its two termini in close proximity. We designed a peptide derived from the disordered termini without the hairpin, termed p53 LinkTer. The LinkTer peptide bound the disordered RT loop of iASPP with the same affinity as the parent p53 Linker peptide, and inhibited the p53-iASPP interaction in vitro. The LinkTer peptide showed increased stability to proteolysis, penetrated cancer cells, caused nuclei shrinkage and decreased cells viability. We conclude that a designed peptide comprising only the IDR from a peptide sequence can be an improved inhibitor since it binds its target protein without the need for pre-folding, paving the way for therapeutic targeting of IDRs.
Extinction rate of discovered and undiscovered plants in Singapore

Extinction is a key issue in the assessment of global biodiversity. However, many extinction rate measures do not account for species that went extinct before they could be discovered. The highly developed island city–state of Singapore has one of the best‐documented tropical floras in the world. This allowed us to estimate the total rate of floristic extinctions in Singapore since 1822 after accounting for sampling effort and crypto extinctions by collating herbaria records. Our database comprised 34,224 specimens from 2076 native species, of which 464 species (22%) were considered nationally extinct. We assumed that undiscovered species had the same annual per‐species extinction rates as discovered species and that no undiscovered species remained extant. With classical and Bayesian algorithms, we estimated that 304 (95% confidence interval, 213–414) and 412 (95% credible interval, 313–534) additional species went extinct before they could be discovered, respectively; corresponding total extinction rate estimates were 32% and 35% (range 30–38%). We detected violations of our 2 assumptions that could cause our extinction estimates, particularly the absolute numbers, to be biased downward. Thus, our estimates should be treated as lower bounds. Our results illustrate the possible magnitudes of plant extirpations that can be expected in the tropics as development continues.
MAML1-Dependent Notch-Responsive Genes Exhibit Differing Cofactor Requirements for Transcriptional Activation

Mastermind proteins are required for transcription of Notch target genes, yet the molecular basis for mastermind function remains incompletely understood. Previous work has shown that Notch can induce transcriptional responses by binding to promoters but more often by binding to enhancers, with HES4 and DTX1 as representative mammalian examples of promoter and enhancer responsiveness, respectively. Here, we show that mastermind dependence of the Notch response at these loci is differentially encoded in Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells. ABSTRACT Mastermind proteins are required for transcription of Notch target genes, yet the molecular basis for mastermind function remains incompletely understood. Previous work has shown that Notch can induce transcriptional responses by binding to promoters but more often by binding to enhancers, with HES4 and DTX1 as representative mammalian examples of promoter and enhancer responsiveness, respectively. Here, we show that mastermind dependence of the Notch response at these loci is differentially encoded in Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells. Knockout of Mastermind-like 1 (MAML1) eliminates Notch-responsive activation of both these genes, and reduced target gene expression is accompanied by a decrease in H3K27 acetylation, consistent with the importance of MAML1 for p300 activity. Add-back of MAML1 variants in knockout cells identifies residues 151 to 350 of MAML1 as essential for expression of either Notch-responsive gene. Fusion of the Notch-binding region of MAML1 to the histone acetyltransferase (HAT) domain of p300 rescues expression of HES4 but not DTX1, suggesting that an additional activity of MAML1 is needed for gene induction at a distance. Together, these studies establish the functional importance of the MAML1 region from residues 151 to 350 for Notch-dependent transcriptional induction and reveal differential requirements for MAML1-dependent recruitment activities at different Notch-responsive loci, highlighting the molecular complexity of Notch-stimulated transcription.
The early diagnosis of alzheimer's disease: From behavioral to genetic study

Alzheimer’s disease, a common form of dementia, is a type of neurodegenerative disease that affects more than 30% of the population older than 85. Clinically, it is characterized as memory loss and cognitive decline. Pathologically, its symptoms include cerebral atrophy, amyloid plaques and NFTs. Generally, the life expectancy is no more than nine years after the definite diagnosis, and life expectancy exceeds 14 years in only 3% of patients. Presently, there is no effective treatment to stop the process; the only measures we can take are to ease or improve symptoms temporarily. Therefore, it is necessary to diagnosis the disease in the early stage, such as through imaging detection via CT, MRI, PET and MSR, or prediction before the disease (genetic examination). However, literature data have supported the notion that Alzheimer’s disease patients show cognitive reserve abilities to some degree. In the future, research perspectives may focus on the cognitive training paradigms in compensatory and restorative strategies. The Early Diagnosis of Alzheimer’s Disease: From Behavioral to Genetic Study Yanna Ren Okayama University, Japan Weiping Yang Hubei University, China & Okayama University, Japan Xiaoyu Tang Liaoning Normal University, China & Okayama University, Japan Fengxia Wu Okayama University, Japan Satoshi Takahashi Okayama University, Japan Jinglong Wu Okayama University, Japan The Early Diagnosis of Alzheimer’s Disease
Cocreating Nursing’s Future: A Leading-Following View

The Institute of Medicine’s (IOM, 2011) Future of Nursing report is an important study of the healthcare system that reflects significant ways nurses may drive transformational change. In this paper, the author explores the Key Elements from the IOM’s (2011) Future of Nursing report in light of Parse’s (2008) leading-following model and community change concepts (Parse, 2003, 2012). This exploration is logical in that to implement the IOM’s Key Elements, community change and leadership are necessary.
Identification of Hub Genes in High-Grade Serous Ovarian Cancer Using Weighted Gene Co-Expression Network Analysis

Background High-grade serous ovarian cancer (HGSOC) is the most malignant gynecologic tumor. This study reveals biomarkers related to HGSOC incidence and progression using the bioinformatics method. Material/Methods Five gene expression profiles were downloaded from GEO. Differentially-expressed genes (DEGs) in HGSOC and normal ovarian tissue samples were screened using limma and the function of DEGs was annotated by KEGG and GO analysis using clusterProfiler. A co-expression network utilizing the WGCNA package was established to define several hub genes from the key module. Furthermore, survival analysis was performed, followed by expression validation with datasets from TCGA and GTEx. Finally, we used single-gene GSEA to detect the function of prognostic hub genes. Results Out of the 1874 DEGs detected from 114 HGSOC versus 49 normal tissue samples, 956 were upregulated and 919 were downregulated. The functional annotation indicated that upregulated DEGs were mostly enriched in cell cycle, whereas the downregulated DEGs were enriched in the MAPK or Ras signaling pathway. Two modules significantly associated with HGSOC were excavated through WGCNA. After survival analysis and expression validation of hub genes, we found that 2 upregulated genes (MAD2L1 and PKD2) and 3 downregulated genes (DOCK5, FANCD2 and TBRG1) were positively correlated with HGSOC prognosis. GSEA for single-hub genes revealed that MAD2L1 and PKD2 were associated with proliferation, while DOCK5, FANCD2, and TBRG1 were associated with immune response. Conclusions We found that FANCD2, PKD2, TBRG1, and DOCK5 had prognostic value and could be used as potential biomarkers for HGSOC treatment.
Agility Training to Integratively Promote Neuromuscular, Cognitive, Cardiovascular and Psychosocial Function in Healthy Older Adults: A Study Protocol of a One-Year Randomized-Controlled Trial

Exercise training effectively mitigates aging-induced health and fitness impairments. Traditional training recommendations for the elderly focus separately on relevant physiological fitness domains, such as balance, flexibility, strength and endurance. Thus, a more holistic and functional training framework is needed. The proposed agility training concept integratively tackles spatial orientation, stop and go, balance and strength. The presented protocol aims at introducing a two-armed, one-year randomized controlled trial, evaluating the effects of this concept on neuromuscular, cardiovascular, cognitive and psychosocial health outcomes in healthy older adults. Eighty-five participants were enrolled in this ongoing trial. Seventy-nine participants completed baseline testing and were block-randomized to the agility training group or the inactive control group. All participants undergo pre- and post-testing with interim assessment after six months. The intervention group currently receives supervised, group-based agility training twice a week over one year, with progressively demanding perceptual, cognitive and physical exercises. Knee extension strength, reactive balance, dual task gait speed and the Agility Challenge for the Elderly (ACE) serve as primary endpoints and neuromuscular, cognitive, cardiovascular, and psychosocial meassures serve as surrogate secondary outcomes. Our protocol promotes a comprehensive exercise training concept for older adults, that might facilitate stakeholders in health and exercise to stimulate relevant health outcomes without relying on excessively time-consuming physical activity recommendations.
A cross-sectional study of periportal fibrosis and Schistosoma mansoni infection among school-aged children in a hard-to-reach area of Madagascar.

BACKGROUND A cross-sectional survey was performed to estimate the prevalence of periportal fibrosis in children based on ultrasound examination in the Marolambo district of the Atsinanana region of Madagascar. This is a remote area known to have a high prevalence of intestinal schistosomiasis. METHODS School-aged children (5-14 y) were selected from six villages for parasitological and sonographic examination. Circulating cathodic antigen (CCA) tests and Kato Katz (KK) stool microscopy were performed. Video-clips of liver views were recorded with a SonoSite iViz and interpreted in the UK by comparison with standardised images (WHO protocol). RESULTS The prevalence of schistosomiasis according to CCA testing was 97.8% (269/275) and 73.8% (203/275) by KK. Sonographic evidence of periportal fibrosis was observed in 11.3% (31/275). The youngest children with fibrosis were aged 6 y. Fibrosis was more common in older children (p=0.03) but was not associated with either infection intensity category (p=0.07) or gender (p=0.67). CONCLUSIONS Findings of periportal fibrosis among children in these hard-to-reach villages suggests chronic Schistosoma mansoni infection from a very young age. This may reflect other similarly remote schistosomiasis-endemic areas and reinforces the need to investigate morbidity in neglected communities to understand the true extent of disease burden in endemic countries.
Ascites: an unusual presentation of eosinophilic gastroenteritis in a child

Eosinophilic ascites, owing to serosal involvement, is a very rare manifestation of eosinophilic gastroenteritis in children, especially when it occurs with muscular involvement in the absence of mucosal disease, which may be confirmed by endoscopic ultrasonography. An 11-year-old girl, presenting with massive eosinophilic ascites and colicky abdominal pain with peripheral eosinophilia, raised IgE levels and positive skin prick test, had such investigation which confirmed the presence of muscle layer thickening of both stomach and small bowel. She responded well to steroids and montelukast.
Shared vision for a decarbonized future energy system in the United States

Significance We explore public perceptions of the current and future energy mixes in the United States. Participants tend to underestimate contributions of oil and natural gas (although coal does not match this pattern) and overestimate contributions of solar and wind to the current national energy mix, problematically misperceiving that the current mix is more decarbonized than it really is. Both conservatives and liberals want a decarbonized future energy mix for 2050—a significant decrease in fossil fuel use and a significant increase in solar and wind energy. Although there is a shared vision of a decarbonized future energy mix, there are strong differences between liberal and conservative participants in their support for policies to achieve this future. How do people envision the future energy system in the United States with respect to using fossil fuels, renewable energy, and nuclear energy? Are there shared policy pathways of achieving a decarbonized energy system? Here, we present results of an online survey (n = 2,429) designed to understand public perceptions of the current and future energy mixes in the United States (i.e., energy sources used for electric power, transportation, industrial, commercial, and residential sectors). We investigate support for decarbonization policies and antidecarbonization policies and the relative importance of climate change as an issue. Surprisingly, we find bipartisan support for a decarbonized energy future. Although there is a shared vision for decarbonization, there are strong partisan differences regarding the policy pathways for getting there. On average, our participants think that climate change is not the most important problem facing the United States today, but they do view climate change as an important issue for the world today and for the United States and the world in the future.
A proposed soft pneumatic actuator control based on angle estimation from data-driven model

This article proposes a bending angle controller for soft pneumatic actuators, which could be implemented in soft robotic rehabilitation gloves to assist patients with hand impairment, such as stroke survivors. A data-driven model is used to estimate the angle as pneumatic pressure is applied to the actuator. Furthermore, a finite element model was used to manually optimize the dimensions of the actuator. An embedded flex sensor, which together with a custom testing rig, was used to gather input data for the data-driven model. This rig contains a pneumatic pressure control circuit as well as a camera for image acquisition. Collected data were fed into a linear regression model to predict the data-driven model. Experiments were carried out to validate model’s accuracy as well as modified proportional–integral–derivative controller angle controller performance. The latter controller is designed to mitigate the non-linear response of solenoid valves at different pressures of the actuator. The data-driven model along with the used controller allows more accurate estimation and quicker response.
Rupture.

sisted of a complex web of systems, each of which relates to a general theme of exploring hidden system structures of the body, environment and computer. change rapidly because of its short orbital periods of about 90 min, while images from geostationary orbit would show a "full" and stationary Earth with day, night and weather patterns coming and going. The intent of this everchanging display is to provide us with a new "world" view that demonstrates a symbiotic relationship between ourselves and our planet and to present the Earth from a perspective in which no single ideology or culture dominates. In addition to the use of various satellites, we propose that future interplanetary probes contain a color video camera that "beams" back the receding view of the Earth-moon system on a continual basis. All images would be arrayed simultaneously on the TV screen so that multiple vantage points in and of space and time are represented. Occasionally, other probes, such as Galileo, might supply spectacular views from, for example, above or below the equatorial (ecliptic) plane. One immediate forum for the distribution of these images would be the Public Broadcasting System in the United States. As a test, college and university public television stations (e.g. WPSX at Pennsylvania State University) would broadcast images from weather satellites and various space shuttle flights to experiment with format, background audio, audience response, etc. To further test the Earthview concept, a cable channel such as C-SPAN (publicaccess TV) would be temporarily dedicated to this exploration-through creative application of art, science and technology-of our relationship to ourselves and our planet.
Early Drug‐Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors

EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high‐throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X‐ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA‐competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.
Modelling Growth and Decline in a Two-Species Model System: Pathogenic Escherichia coli O157:H7 and Psychrotrophic Spoilage Bacteria in Milk

Shiga toxin-producing Escherichia coli O157:H7 is a food-borne pathogen and the major cause of hemorrhagic colitis. Pseudomonas is the genus most frequent psychrotrophic spoilage microorganisms present in milk. Two-species bacterial systems with E. coli O157:H7, non-pathogenic E. coli, and P. fluorescens in skimmed milk at 7, 13, 19, or 25 °C were studied. Bacterial interactions were modelled after applying a Bayesian approach. No direct correlation between P. fluorescens’s growth rate and its effect on the maximum population densities of E. coli species was found. The results show the complexity of the interactions between two species in a food model. The use of natural microbiota members to control foodborne pathogens could be useful to improve food safety during the processing and storage of refrigerated foods.