Miracle-dz/UniFAR-FTUs huggingface dataset:
Leveraging cues from person-generated health data for peer matching in online communities

OBJECTIVE Online health communities offer a diverse peer support base, yet users can struggle to identify suitable peer mentors as these communities grow. To facilitate mentoring connections, we designed a peer-matching system that automatically profiles and recommends peer mentors to mentees based on person-generated health data (PGHD). This study examined the profile characteristics that mentees value when choosing a peer mentor. MATERIALS AND METHODS Through a mixed-methods user study, in which cancer patients and caregivers evaluated peer mentor recommendations, we examined the relative importance of four possible profile elements: health interests, language style, demographics, and sample posts. Playing the role of mentees, the study participants ranked mentors, then rated both the likelihood that they would hypothetically contact each mentor and the helpfulness of each profile element in helping the make that decision. We analyzed the participants' ratings with linear regression and qualitatively analyzed participants' feedback for emerging themes about choosing mentors and improving profile design. RESULTS Of the four profile elements, only sample posts were a significant predictor for the likelihood of a mentee contacting a mentor. Communication cues embedded in posts were critical for helping the participants choose a compatible mentor. Qualitative themes offer insight into the interpersonal characteristics that mentees sought in peer mentors, including being knowledgeable, sociable, and articulate. Additionally, the participants emphasized the need for streamlined profiles that minimize the time required to choose a mentor. CONCLUSION Peer-matching systems in online health communities offer a promising approach for leveraging PGHD to connect patients. Our findings point to interpersonal communication cues embedded in PGHD that could prove critical for building mentoring relationships among the growing membership of online health communities.
Cognitive computing for the automated extraction and meaningful use of health data in narrative medical notes: An application to the clinical management of hearing impaired aged patients

It is currently estimated that 80% of health data, such as that coming from medical transcripts, medical notes, lab results, email messages, attachments, is unstructured. Being unstructured, this information cannot be processed through automated PC procedures but requires the interpretation of human beings. We propose a cognitive computing system to extract automatically meaningful health information from the textual documents of the patient folder and merge this information into a structured data frame. The system was tested on the medical documents generated in an audiological outpatient hospital service; the data corpus consisted of the documents and reports generated longitudinally from the enrollment visit to the last available follow-up of hearing impaired aged patients treated with cochlear implants (CI). The system is based on an Information Extraction (IE) module to extract meaningful health information, a couple of ontologies to interpret the meaning and classify the extracted information into a logical hierarchy and an ad hoc developed structured data frame to gather the information. The system was designed to be compliant with the clinical best practices of the audiological/ENT (Ear-Nose-Throat) medical domains to ensure its ease of use in the real practice. The performance was assessed by measuring the percentage of information correctly extracted by the system against the one manual extracted by two experts. The accuracy of the system was very good (recall= 0.78; precision=3D0.95).
RNA Binding of Ebola Virus VP30 Is Essential for Activating Viral Transcription

ABSTRACT The template for Ebola virus (EBOV) transcription and replication is the helical viral nucleocapsid composed of the viral negative-sense (−) RNA genome, which is complexed by the nucleoprotein (NP), VP35, polymerase L, VP24, and VP30. While viral replication is exerted by polymerase L and its cofactor VP35, EBOV mRNA synthesis is regulated by the viral nucleocapsid protein VP30, an essential EBOV-specific transcription factor. VP30 is a homohexameric phosphoprotein containing a nonconventional zinc finger. The transcriptional support activity of VP30 is strongly influenced by its phosphorylation state. We studied here how RNA binding contributed to VP30's function in transcriptional activation. Using a novel mobility shift assay and the 3′-terminal 154 nucleotides of the EBOV genome as a standard RNA substrate, we detected that RNA binding of VP30 was severely impaired by VP30 mutations that (i) destroy the protein's capability to form homohexamers, (ii) disrupt the integrity of its zinc finger domain, (iii) mimic its fully phosphorylated state, or (iv) alter the putative RNA binding region. RNA binding of the mutant VP30 proteins correlated strongly with their transcriptional support activity. Furthermore, we showed that the interaction between VP30 and the polymerase cofactor VP35 is RNA dependent, while formation of VP30 homohexamers and VP35 homotetramers is not. Our data indicate that RNA binding of VP30 is essential for its transcriptional support activity and stabilizes complexes of VP35/L polymerase with the (−) RNA template to favor productive transcriptional initiation in the presence of termination-active RNA secondary structures. IMPORTANCE Ebola virus causes severe fevers with unusually high case fatality rates. The recent outbreak of Ebola virus in West Africa claimed more than 11,000 lives and threatened to destabilize a whole region because of its dramatic effects on the public health systems. It is currently not completely understood how Ebola virus manages to balance viral transcription and replication in the infected cells. This study shows that transcriptional support activity of the Ebola virus transcription factor VP30 is highly correlated with its ability to bind viral RNA. The interaction between VP30 and VP35, the Ebola virus polymerase cofactor, is dependent on the presence of RNA as well. Our data contribute to the understanding of the dynamic interplay between nucleocapsid proteins and the viral RNA template in order to promote viral RNA synthesis.
Bat Severe Acute Respiratory Syndrome-Like Coronavirus WIV1 Encodes an Extra Accessory Protein, ORFX, Involved in Modulation of the Host Immune Response

ABSTRACT Bats harbor severe acute respiratory syndrome (SARS)-like coronaviruses (SL-CoVs) from which the causative agent of the 2002-2003 SARS pandemic is thought to have originated. However, despite the fact that a large number of genetically diverse SL-CoV sequences have been detected in bats, only two strains (named WIV1 and WIV16) have been successfully cultured in vitro. These two strains differ from SARS-CoV only in containing an extra open reading frame (ORF) (named ORFX), between ORF6 and ORF7, which has no homology to any known protein sequences. In this study, we constructed a full-length cDNA clone of SL-CoV WIV1 (rWIV1), an ORFX deletion mutant (rWIV1-ΔX), and a green fluorescent protein (GFP)-expressing mutant (rWIV1-GFP-ΔX). Northern blotting and fluorescence microscopy indicate that ORFX was expressed during WIV1 infection. A virus infection assay showed that rWIV1-ΔX replicated as efficiently as rWIV1 in Vero E6, Calu-3, and HeLa-hACE2 cells. Further study showed that ORFX could inhibit interferon production and activate NF-κB. Our results demonstrate for the first time that the unique ORFX in the WIV1 strain is a functional gene involving modulation of the host immune response but is not essential for in vitro viral replication. IMPORTANCE Bats harbor genetically diverse SARS-like coronaviruses (SL-CoVs), and some of them have the potential for interspecies transmission. A unique open reading frame (ORFX) was identified in the genomes of two recently isolated bat SL-CoV strains (WIV1 and -16). It will therefore be critical to clarify whether and how this protein contributes to virulence during viral infection. Here we revealed that the unique ORFX is a functional gene that is involved in the modulation of the host immune response but is not essential for in vitro viral replication. Our results provide important information for further exploration of the ORFX function in the future. Moreover, the reverse genetics system we constructed will be helpful for study of the pathogenesis of this group of viruses and to develop therapeutics for future control of emerging SARS-like infections.
TOXICOLOGICAL PERSPECTIVE ON THE OSMOREGULATION AND IONOREGULATION PHYSIOLOGY OF MAJOR IONS BY FRESHWATER ANIMALS: TELEOST FISH, CRUSTACEA, AQUATIC INSECTS, AND MOLLUSCA

Anthropogenic sources increase freshwater salinity and produce differences in constituent ions compared with natural waters. Moreover, ions differ in physiological roles and concentrations in intracellular and extracellular fluids. Four freshwater taxa groups are compared, to investigate similarities and differences in ion transport processes and what ion transport mechanisms suggest about the toxicity of these or other ions in freshwater. Although differences exist, many ion transporters are functionally similar and may belong to evolutionarily conserved protein families. For example, the Na+/H+‐exchanger in teleost fish differs from the H+/2Na+ (or Ca2+)‐exchanger in crustaceans. In osmoregulation, Na+ and Cl− predominate. Stenohaline freshwater animals hyperregulate until they are no longer able to maintain hypertonic extracellular Na+ and Cl− concentrations with increasing salinity and become isotonic. Toxic effects of K+ are related to ionoregulation and volume regulation. The ionic balance between intracellular and extracellular fluids is maintained by Na+/K+‐adenosine triphosphatase (ATPase), but details are lacking on apical K+ transporters. Elevated H+ affects the maintenance of internal Na+ by Na+/H+ exchange; elevated HCO3− inhibits Cl− uptake. The uptake of Mg2+ occurs by the gills or intestine, but details are lacking on Mg2+ transporters. In unionid gills, SO42− is actively transported, but most epithelia are generally impermeant to SO42−. Transporters of Ca2+ maintain homeostasis of dissolved Ca2+. More integration of physiology with toxicology is needed to fully understand freshwater ion effects. Environ Toxicol Chem 2017;36:576–600. © 2016 The Authors. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Molecular Evolution of Human Immunodeficiency Virus env in Humans and Monkeys: Similar Patterns Occur during Natural Disease Progression or Rapid Virus Passage

ABSTRACT Neonatal rhesus macaque 95-3 was inoculated with nonpassaged simian-human immunodeficiency virus strain SHIV-vpu+, which encodes env of the laboratory-adapted human immunodeficiency virus (HIV) strain IIIB and is considered nonpathogenic. CD4+ T-cell counts dropped to <200 cells/μl within 4.6 years, and monkey 95-3 died with opportunistic infections 5.9 years postinoculation. Transfer of blood from 95-3 to two naive adult macaques resulted in high peak viral loads and rapid, persistent T-cell depletion. Progeny virus evolved in 95-3 despite high SHIV-vpu+ neutralizing antibody titers and still used CXCR4 but, in contrast to parental SHIV-vpu+, productively infected macrophages and resisted neutralization. Sequence analysis revealed three new potential glycosylation sites in gp120; another two were lost. Strikingly similar mutations were detected in a laboratory worker who progressed to AIDS after accidental HIV-IIIB infection (T. Beaumont et al., J. Virol. 75:2246-2252, 2001), thus supporting the SHIV-vpu+/rhesus macaque system as a relevant model. Similar mutations were also described after rapid passage of chimeric viruses encoding IIIB env in rhesus and pig-tailed macaques (M. Cayabyab et al., J. Virol. 73:976-984, 1999; Z. Q. Liu et al., Virology 260:295-307, 1999; S. V. Narayan et al., Virology 256:54-63, 1999; R. Raghavan et al., Brain Pathol. 7:851-861, 1997; E. B. Stephens et al., Virology 231:313-321, 1997). Thus, HIV-IIIB env evolved similarly in three different species; this selection occurred in chronically infected individuals during disease progression as well as after rapid virus passage. We postulate that evolutionary pressure led to the outgrowth of more aggressive viral variants in all three species.
ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells

Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated anti-EGFR monoclonal antibodies imgatuzumab and cetuximab–induced internalization and membranous turnover of EGFR, and whether this affected imgatuzumab–mediated ADCC responses and growth inhibition of non-small cell lung cancer (NSCLC) cells. In a panel of wild-type EGFR expressing human NSCLC cell lines, membranous and total EGFR levels were downregulated more effectively by imgatuzumab when compared with cetuximab. Imgatuzumab plus cetuximab enhanced EGFR internalization and reduced membranous turnover of EGFR, resulting in an even stronger downregulation of EGFR. Immunofluorescent analysis showed that combined treatment increased clustering of receptor-antibody complexes and directed internalized EGFR to lysosomes. The antibody combination potently inhibited intracellular signaling and epidermal growth factor (EGF)-dependent cell proliferation. More importantly, robust EGFR downregulation after 72 hours with the antibody combination did not impair ADCC responses. In conclusion, imgatuzumab plus cetuximab leads to a strong downregulation of EGFR and superior cell growth inhibition in vitro without affecting antibody-induced ADCC responses. These findings support further clinical exploration of the antibody combination in EGFR wild-type NSCLC.
Making a Customized DIY-Computer with Infobricks

Making is about learning new skills, creative explorations, and solving problems; but it is also about giving and caring for others. Many makers enjoy creating unique and bespoke presents to give them to people they care about to enrich their life. To support and exploit this motivation, we designed a modular toolkit named Infobricks, which was conceived for creating DIY and accessible computers. For a grounded requirements gathering of Infobricks, we conducted a study featuring six makers. We present a functional prototype for Infobricks as an embodiment of the findings from this study. Moreover, we illustrate Infobricks in a “lived scenario” featuring one additional participant who used the kit to create a computer for her older mother. Overall, our ambition in this paper is to design a toolkit like Infobricks and to demonstrate how it can provide e.g. senior citizens with customized computers by drawing on the constructive energy and skillset of makers.
Is alcohol consumption related to likelihood of reporting chronic widespread pain in people with stable consumption? Results from UK biobank

Abstract Studies have suggested that alcohol consumption is strongly related to reduced reporting of chronic widespread pain (CWP) and level of disability in people with CWP or fibromyalgia. Direction of causality has not been established, that is whether the association is due to people's health influencing their alcohol consumption or vice versa. UK Biobank recruited over 500,000 people aged 40 to 69 years, registered at medical practices nationwide. Participants provided detailed information on health and lifestyle factors including pain and alcohol consumption. Total units consumed per week were calculated for current drinkers. Information was also collected on changes in alcohol consumption and reasons for such changes. Analysis was performed with logistic regression expressed as odds ratios (ORs) with 95% confidence intervals, then adjusted for a large number of potential confounding factors (adjORs). In males who reported drinking the same as 10 years previously, there was a U-shaped relationship between amount drunk and odds of reporting CWP (nondrinkers CWP prevalence 2.4%, 19.1-32.1 units/wk 0.4%, >53.6 units/wk 1.0%; adjORs 2.53 95% confidence intervals [1.78-3.60] vs 1 vs 1.52 [1.05-2.20]). In females, there was a decrease in the proportion reporting CWP up to the modal category of alcohol consumption with no further change in those drinking more (nondrinkers CWP prevalence 3.4%, 6.4-11.2 units/wk 0.7%, >32.1 units/wk 0.7%; adjORs 2.11 [1.67-2.66] vs 1 vs 0.86 [0.54-1.39]). This large study has shown a clear relationship between alcohol consumption and reporting of pain even in people who had not reported changing consumption because of health concerns, after adjustment for potential confounding factors.
Activating the Chromatin by Noncoding RNAs.

SIGNIFICANCE The extent and breadth of transcription have recently been uncovered and this has revealed an extensive array of noncoding RNAs (ncRNAs). The biological role and significance of these ncRNAs have been realized and to date it appears that ncRNAs may have many important regulatory functions. ncRNAs are multifaceted and they induce a complexity of different types of transcriptional and posttranscriptional regulation, including gene activation. Recent Advances: Association of ncRNAs with gene activation is an important finding. Not only enhancer RNA (eRNA) but other types of ncRNAs, including small RNA (sRNA), long-noncoding RNA (lncRNA), microRNA (miRNA), and PIWI-associated RNA (piRNA), have also been implicated in gene activation. Interestingly, they often coincide with histone modifications that favor an open chromatin. In addition, these ncRNAs can recruit key factors important for transcription, including RNA polymerase II. They may directly bind the genomic DNA or act as scaffolds; alternatively, they may loop the chromatin to enhance transcription. CRITICAL ISSUES Although the role of small activating (sa)RNAs has been considerably studied, the roles of miRNAs and piRNAs in gene activation still need to be substantiated and issues of specificity require further studies. FUTURE DIRECTIONS The ncRNA field is coming out of its infancy and we are gaining a global picture of the importance of ncRNAs. However, detailed mechanisms of action of the different ncRNAs are still to be determined. This may reveal novel ways of transcriptional regulation, which will facilitate our ability to utilize these regulatory pathways for research and therapeutic purposes. Antioxid. Redox Signal. 29, 813-831.
Systemic delivery of factor IX messenger RNA for protein replacement therapy

Significance Abnormal gene expression is the underlying cause for many pathological states, and restoring normalcy through overexpression or knockdown is a conceptually simple solution. Despite the advantages over DNA and viral vectors, RNA-based therapeutics have been plagued by problems of poor translatability, stability, and adverse immune reactions. Efficient in vivo delivery has also been challenging because currently available lipid nanoparticles (LNPs) can induce liver damage and elicit a strong immune response. In this study, we demonstrate the successful use of LUNAR—a safe, reproducible, and effective LNP mRNA delivery platform that can be used to treat diseases requiring protein replacement. We achieve therapeutic delivery of mRNAs in a preclinical model of hemophilia and demonstrate alleviation of disease symptoms. Safe and efficient delivery of messenger RNAs for protein replacement therapies offers great promise but remains challenging. In this report, we demonstrate systemic, in vivo, nonviral mRNA delivery through lipid nanoparticles (LNPs) to treat a Factor IX (FIX)-deficient mouse model of hemophilia B. Delivery of human FIX (hFIX) mRNA encapsulated in our LUNAR LNPs results in a rapid pulse of FIX protein (within 4–6 h) that remains stable for up to 4–6 d and is therapeutically effective, like the recombinant human factor IX protein (rhFIX) that is the current standard of care. Extensive cytokine and liver enzyme profiling showed that repeated administration of the mRNA–LUNAR complex does not cause any adverse innate or adaptive immune responses in immune-competent, hemophilic mice. The levels of hFIX protein that were produced also remained consistent during repeated administrations. These results suggest that delivery of long mRNAs is a viable therapeutic alternative for many clotting disorders and for other hepatic diseases where recombinant proteins may be unaffordable or unsuitable.
OpenFlow Communications and TLS Security in Software-Defined Networks

The adoption of Software-Defined Networking (SDN), a networking approach where data traffic control and execution are made independent of each other, is an ongoing process that some companies are considering as an option but have not embraced yet due to different factors. Incorporating this new paradigm into an existing network defines a shift in networking technology with different benefits expected to derive from this implementation. These benefits include (1) the ability to use customised business specific applications, (2) reduce overhead costs on legacy network infrastructure, taking full control of network, (3) reduce network application update time, increase productivity, and (4) apply increased security among others. However, the security of SDN itself has been a subject of debate. This is mainly because, the communication standard used by SDN, known as OpenFlow, and developed by the Open Network Foundation, does not enforce the implementation of the Transport Layer Security (TLS) but defines it only as optional. This could then make the network infrastructure vulnerable and therefore affect the overall security of a company. Security plays a significant part in an organisation and it is one of the determinants of the success of SDN. OpenFlow security relies on the implementation of TLS, which has been proven vulnerable, and therefore bringing to mind the question on how secure organisation's data is when the implementation of secure data transfer is treated with laxity. This paper focuses on securing OpenFlow communication in SDN by summarising TLS security flaws and recommending ways of improving TLS security thereby securing OpenFlow communication.
Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia

Abstract Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and long-lasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels.