Miracle-dz/UniFAR-FTUs huggingface dataset:
IL-10 Restricts Memory T Cell Inflation during Cytomegalovirus Infection

The β-herpesvirus CMV induces a substantial and progressive expansion of virus-specific memory CD8 T cells, which protect the host against viral reactivation from latency. In this paper, we report that this expansion, or “inflation,” of memory T cells is amplified dramatically during mouse CMV infection of IL-10 knockout (IL-10−/−) mice. T cells from IL-10−/− mice were oligoclonal, exhibited a highly activated phenotype, expressed antiviral cytokines, and degranulated in response to cognate Ag encounter ex vivo. Moreover, latent viral load was reduced in IL-10−/− mice. Importantly, these results were recapitulated by IL-10R blockade during chronic/latent infection of wild-type mice. These data demonstrate that regulatory immune mechanisms can influence CMV-specific T cell memory and suggest a possible rationale for the acquisition of functional IL-10 orthologs by herpesviruses.
FIELD WORKERS AT THE INTERFACE

This issue of Developing World Bioethics includes a collection of papers on intermediary staff and volunteers working at the interface between research institutions and researchers, and the communities from which research participants are recruited. ‘Field worker’ – a short hand commonly used in many research settings – refers here to those whose main role is face-to-face engagement with participants, who usually speak the participants’ first language, who are from or live in the study areas, and whose work entails moving around the study areas or health facilities. Field workers can be differentiated from medical or scientific staff for whom only part of their duties entail direct interaction with participants, and who are primarily based in the research institution or the clinic. In international research settings field workers are variously called research assistants, community interviewers, data collectors, fieldworkers, field assistants, assessors, follow up staff or defaulter tracers. Although some may hold first degrees or certificates, many are secondary school leavers without higher education opportunity; overall they are formally less qualified than clinical and research staff. Instead, field workers often have extensive informal training and experience from earlier volunteering and jobs in research centres or the NGO sector, which often require similar tasks and expertise.1 Their roles may include communicating about studies and mobilisation and follow-up of participants, conducting interviews, and carrying out relatively simple biomedical data-collection procedures such as taking temperatures and collecting finger prick blood samples.
The Adaptor Protein CIKS/Act1 Is Essential for IL-25-Mediated Allergic Airway Inflammation1

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.
The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance

ABSTRACT Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir protein-independent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.
A Comparison of Danish and Canadian Consumer Medication Information

Many people around the world use prescription medications. Consumers often require information about their medications to support taking them safely and effectively. One source of such information is Consumer Medication Information (CMI). Canadians typically receive printed CMI when a new prescription is filled whereas Danes have the online resource min.medicin. dk. This study compared the content and design of Danish and Canadian CMI. Danish CMI satisfied seven of the 11 content utility criteria (developed in previous work) identified as supporting the safe and effective medication use. However, Danish CMI provided a more information about how frequently possible side effects occur and multimedia (e.g., images, videos) directions for some medications. This study examined some of the similarities and differences between how Canadians and Danes are informed about medications. However, further research is required to determine what content and methods of delivery are most beneficial in supporting safe and effective medication use.
A systematic review of satisfaction with teledermatology

Background The two most commonly used modalities of teledermatology (TD) are store-and-forward (SF) and live–interactive (LI) TD. Existing studies have not compared these tools with respect to patient and provider satisfaction. Objective To systematically review all published studies of patient and provider satisfaction with SF and LI TD. Methods PubMed, EMBASE, and Cochrane databases were systematically searched for studies on provider or patient satisfaction with SF or LI TD between January 2000 and June 2016. Results Forty eligible studies were identified: 32 with SF TD, 10 with LI TD, and 2 evaluating both. With SF TD, 96% of studies assessing patient satisfaction and 82% of studies assessing provider satisfaction demonstrated satisfaction (n = 24 and 17, respectively). With LI TD, 89% of studies assessing patient satisfaction and all studies assessing provider satisfaction revealed satisfaction (n = 9 and 6, respectively). Conclusion Patients and providers are satisfied with both SF and LI TD. Studies assessing satisfaction with LI have not been conducted in recent years, and have only been conducted in limited geographic patient populations. Further research assessing satisfaction with TD will help address any dissatisfaction with its uses and allow for increased support and funding of future programmes.
Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene

Essentials Anti‐factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8TKO mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8TKO mice will aid in studying FVIII inhibitor formation.
Gender Disparities in Ocular Inflammatory Disorders*

Abstract Ocular inflammatory disorders disproportionately affect women, and the majority of affected women are of childbearing age. The role of sex or reproductive hormones has been proposed in many other inflammatory or autoimmune disorders, and findings from non-ocular autoimmune diseases suggest a complex interaction between sex hormones, genetic factors and the immune system. However, despite the age and sex bias, factors that influence this disparity are complicated and unclear. This review aims to evaluate the gender disparities in prevalence, incidence and severity of the most common infectious and non-infectious ocular inflammatory disorders.
Vandetanib, Designed to Inhibit VEGFR2 and EGFR Signaling, Had No Clinical Activity as Monotherapy for Recurrent Ovarian Cancer and No Detectable Modulation of VEGFR2

Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. Experimental Design: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples. Results: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed. Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib. Clin Cancer Res; 16(2); 664–72
Detection of Human CYP2C8, CYP2C9, and CYP2J2 in Cardiovascular Tissues

The cytochrome P450 (P450) enzymes CYP2C8, CYP2C9, and CYP2J2 metabolize arachidonic acid to epoxyeicosatrienoic acids, which are known to be vital in regulation of vascular tone and cardiovascular homeostasis. Because there is limited information regarding the relative expression of these P450 enzymes in cardiovascular tissues, this study examined the expression of CYP2C8, CYP2C9, and CYP2J2 mRNA and protein in human heart, aorta, and coronary artery samples by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. CYP2J2 and CYP2C9 mRNA levels were highly variable in human hearts, whereas CYP2C8 mRNA was present in lower abundance. CYP2J2 mRNA was approximately 103 times higher than CYP2C9 or CYP2C8 in human heart. However, CYP2C9 mRNA was more abundant than CYP2J2 or CYP2C8 in one ischemic heart. In human aorta, mean CYP2C9 mRNA levels were ∼50 times higher than that of CYP2J2 and 5-fold higher than that of CYP2C8. In human coronary artery, mean values for CYP2C9 mRNA were ∼2-fold higher than that of CYP2J2 mRNA and 6-fold higher than that of CYP2C8 mRNA. Immunoblotting results show relatively high levels of CYP2J2 and CYP2C8 protein in human hearts, which was confirmed by immunohistochemistry. CYP2C9 protein was also detected at high levels in one ischemic heart by immunoblotting. CYP2C9 was present at higher levels than CYPJ2 in aorta and coronary artery, whereas CYP2C8 protein was below the limits of detection. The expression of CYP2J2 and CYP2C8 in human heart, and CYPC9 and CYP2J2 in aorta and coronary artery is consistent with a physiological role for these enzymes in these tissues.
Compound Interest: Assessing the Effects of Chemical Mixtures in Vivo

Humans are exposed to mixtures of chemicals through food, air, water, dust, and household and personal care products. In most cases, little is known about the combined effects of potentially harmful chemicals. A mouse study in Environmental Health Perspectives tested whether one constituent of a chemical mixture might alter tissue levels of the others. If so, the effects of the mixture on the mouse’s health might be different from the effects that would be predicted based on the effects of each chemical by itself. Such information is important when assessing the potential health risks of chemical mixtures to which the public may be exposed. For their experiment, the researchers selected three chemicals to which the public is often exposed: bisphenol A (BPA), triclosan, and tetrabromobisphenol A (TBBPA). BPA is a component of some plastics and epoxy resins that are used to make food and beverage packaging. Triclosan is an antibacterial agent found in multiple personal care products and other items, although it has been removed from over-the-counter soaps sold in the United States. TBBPA, a widely used brominated flame retardant, is often found in house dust. The scientists chose these particular chemicals because “they are common human exposures that are known to have some estrogenic action,” says senior study author Denys deCatanzaro, a toxicologist at McMaster University in Ontario, Canada. Previously, deCatanzaro’s team showed that triclosan alone could elevate BPA levels in the reproductive tissues of male and female mice. Toxicologists have traditionally focused on the effects of one chemical at a time. This approach can be useful for determining the molecular pathways through which a particular chemical may produce an effect, according to lead study author Tyler Pollock, a PhD candidate at McMaster. However, this approach can overlook health effects of that chemical after coexposures, Pollock says. In a series of three experiments, the researchers subcutaneously injected mice with TBBPA, triclosan, or both; the study used doses much larger than typical human exposures. Then, they fed the mice a radiolabeled form of BPA in a dietary supplement. Although every effort is made to eliminate BPA from the environment of laboratory animals, some may remain in food, bedding, and dust, deCatanzaro says. Using a radioactive tracer helps researchers account for background levels by ensuring that they measure only the doses administered during the experiment.
Reconstitution of CO2 Regulation of SLAC1 Anion Channel and Function of CO2-Permeable PIP2;1 Aquaporin as CARBONIC ANHYDRASE4 Interactor

Functional reconstitution of extracellular CO2 signaling to ion channel regulation is shown by expression of SLAC1, protein kinases, CARBONIC ANHYDRASE4, and interacting CO2-permeable PIP2;1 aquaporin in X. laevis oocytes. Dark respiration causes an increase in leaf CO2 concentration (Ci), and the continuing increases in atmospheric [CO2] further increases Ci. Elevated leaf CO2 concentration causes stomatal pores to close. Here, we demonstrate that high intracellular CO2/HCO3− enhances currents mediated by the Arabidopsis thaliana guard cell S-type anion channel SLAC1 upon coexpression of any one of the Arabidopsis protein kinases OST1, CPK6, or CPK23 in Xenopus laevis oocytes. Split-ubiquitin screening identified the PIP2;1 aquaporin as an interactor of the βCA4 carbonic anhydrase, which was confirmed in split luciferase, bimolecular fluorescence complementation, and coimmunoprecipitation experiments. PIP2;1 exhibited CO2 permeability. Mutation of PIP2;1 in planta alone was insufficient to impair CO2- and abscisic acid-induced stomatal closing, likely due to redundancy. Interestingly, coexpression of βCA4 and PIP2;1 with OST1-SLAC1 or CPK6/23-SLAC1 in oocytes enabled extracellular CO2 enhancement of SLAC1 anion channel activity. An inactive PIP2;1 point mutation was identified that abrogated water and CO2 permeability and extracellular CO2 regulation of SLAC1 activity. These findings identify the CO2-permeable PIP2;1 as key interactor of βCA4 and demonstrate functional reconstitution of extracellular CO2 signaling to ion channel regulation upon coexpression of PIP2;1, βCA4, SLAC1, and protein kinases. These data further implicate SLAC1 as a bicarbonate-responsive protein contributing to CO2 regulation of S-type anion channels.
People With Autism Spectrum Conditions Make More Consistent Decisions

People with autism spectrum conditions (ASC) show reduced sensitivity to contextual stimuli in many perceptual and cognitive tasks. We investigated whether this also applies to decision making by examining adult participants’ choices between pairs of consumer products that were presented with a third, less desirable “decoy” option. Participants’ preferences between the items in a given pair frequently switched when the third item in the set was changed, but this tendency was reduced among individuals with ASC, which indicated that their choices were more consistent and conventionally rational than those of control participants. A comparison of people who were drawn from the general population and who varied in their levels of autistic traits revealed a weaker version of the same effect. The reduced context sensitivity was not due to differences in noisy responding, and although the ASC group took longer to make their decisions, this did not account for the enhanced consistency of their choices. The results extend the characterization of autistic cognition as relatively context insensitive to a new domain, and have practical implications for socioeconomic behavior.
Work ability is influenced by kinesiophobia among patients with persistent pain

ABSTRACT The purpose of this study was to investigate how kinesiophobia fluctuates in patients over a four weeks multimodal rehabilitation program and to study the relationship between work ability and kinesiophobia. The study included 112 patients (94 women, 18 men). Measurements were made before, directly after, 2 months after, and 12 months after the program. The level of work ability was rated by the patients on a scale from 0% to 100%, and kinesiophobia was measured by the Swedish version of the Tampa Scale for Kinesiophobia (TSK-SV). Kinesiophobia decreased between the start of the multimodal rehabilitation program and the follow-up periods. Work ability increased over time, but not between baseline and the 2-month follow-up. Decreases in the TSK-SV score between baseline and the 2-month follow-up were related to the increased probability of improved work ability at the 12-month follow-up. In conclusion, a decrease in kinesiophobia seems to be related to increased work ability of patients participating in a 4-week multimodal rehabilitation program.
‘The moment I leave my home – there will be massive challenges’: experiences of living with a spinal cord injury in Botswana

Abstract Background: When suffering a spinal cord injury (SCI), the patient and family face numerous challenges regardless of socio-economic level. The stigmatisation of persons with disabilities has been reported, however, reports from Southern Africa are largely lacking. Purpose: To explore the experiences of living with a traumatic SCI in Botswana concerning perceived attitudes, obstacles and challenges. Method: A qualitative approach with semi-structured interviews was conducted. Thirteen community-dwelling persons who have lived with an SCI for at least two years participated. Results: A theoretical model was formed that illustrate the associations between the core category, Self, and the categories Relationships and Society. The model illustrates that personal resources, including a strong identity and a positive attitude, are crucial to the experience of inclusion in the community. A supportive family, a source of income, and faith were strong facilitators, while inaccessibility and devaluing attitudes were barriers. Having a disability led to increased risk of poverty and social exclusion. Conclusion: This study emphasised the importance of personal resources, family support, and improved accessibility to facilitate inclusion in the society. Informants requested legislation to advocate for the rights of persons with disabilities to be respected, with the aim of moving towards an equal accessible society. Implications for Rehabilitation Reclaiming or restructuring one’s identity after a SCI is crucial for the person’s ability to move on and develop beneficial coping strategies. Support from family and friends, staff and peer support are crucial parts in that process. Spirituality, values, needs and coping strategies vary profoundly among persons sustaining disabling injuries. In striving to optimise care, rehabilitation staff needs to be attentive to the personal resources and preferences to be able to individualise care, encounter, and facilitate transition back to the community. Family members play a crucial part in rehabilitation. It is essential for the patients’ well-being and care that they get explicit descriptions of the patient’s abilities. Living in a well-adapted home will facilitate well-being, independence, and return to work. Rehabilitation staff needs to focus their efforts on making this successful prior to discharge from hospital.
The 2022 hormone therapy position statement of The North American Menopause Society

Abstract “The 2022 Hormone Therapy Position Statement of The North American Menopause Society” (NAMS) updates “The 2017 Hormone Therapy Position Statement of The North American Menopause Society” and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women’s health and menopause was recruited by NAMS to review the 2017 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Advisory Panel’s recommendations were reviewed and approved by the NAMS Board of Trustees. Hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing therapy. For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome VMS and prevention of bone loss. For women who initiate hormone therapy more than 10 years from menopause onset or who are aged older than 60 years, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS, with shared decision-making and periodic reevaluation. For bothersome genitourinary syndrome of menopause symptoms not relieved with over-the-counter therapies in women without indications for use of systemic hormone therapy, low-dose vaginal estrogen therapy or other therapies (eg, vaginal dehydroepiandrosterone or oral ospemifene) are recommended.