Miracle-dz/UniFAR-FTUs huggingface dataset:
Stabilization of the gp120 V3 loop through hydrophobic interactions reduces the immunodominant V3-directed non-neutralizing response to HIV-1 envelope trimers

To provide protective immunity against circulating primary HIV-1 strains, a vaccine most likely has to induce broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) spike. Recombinant Env trimers such as the prototype BG505 SOSIP.664 that closely mimic the native Env spike can induce autologous neutralizing antibodies (NAbs) against relatively resistant (tier 2) primary viruses. Ideally, Env immunogens should present broadly neutralizing antibody epitopes but limit the presentation of immunodominant non-NAb epitopes that might induce off-target and potentially interfering responses. The V3 loop in gp120 is such a non-NAb epitope that can effectively elicit non-NAbs when animals are immunized with SOSIP.664 trimers. V3 immunogenicity can be diminished, but not abolished, by reducing the conformational flexibility of trimers via targeted sequence changes, including an A316W substitution in V3, that create the SOSIP.v4. 1 and SOSIP.v5. 2 variants. Here, we further modified these trimer designs by introducing leucine residues at V3 positions 306 and 308 to create hydrophobic interactions with the tryptophan residue at position 316 and with other topologically proximal sites in the V1V2 domain. Together, these modifications further stabilized the resulting SOSIP.v5. 2 S306L/R308L trimers in the prefusion state in which V3 is sequestered. When we tested these trimers as immunogens in rabbits, the induction of V3 non-NAbs was significantly reduced compared with the SOSIP.v5. 2 trimers and even more so compared with the SOSIP.664 prototype, without affecting the autologous NAb response. Hence, these additional trimer sequence modifications may be beneficial for immunization strategies that seek to minimize off-target non-NAb responses.
A screening instrument for autism at 18 months of age: a 6-year follow-up study.

OBJECTIVES A population of 16,235 children aged 18 months was screened using the Checklist for Autism in Toddlers (CHAT) to identify childhood autism (CA). Two further screening procedures were conducted at age 3 and 5 years. The population was followed up at age 7 years in order to establish the sensitivity, specificity, and positive predictive value of the instrument. METHOD A brief checklist assessing joint attention and pretend play behaviors was administered by primary health care practitioners when the children were 18 months old. Follow-up methods included screening through parents and health practitioners and checking medical and educational records. RESULTS Nineteen cases of CA were successfully identified by the CHAT at 18 months. At follow-up a total of 50 cases of CA were identified via all surveillance methods. Thus, the CHAT has a sensitivity of 38% and a specificity of 98% for identifying CA. The positive predictive value of the instrument was maximized by concentration on the highest-risk group. Repeated screening 1 month later increased the positive predictive value to 75% for identification of CA but reduced the sensitivity to 20%, although the specificity was close to 100%. The screen also identified cases of pervasive developmental disorder as well as children with language and other developmental disorders. CONCLUSIONS The CHAT can be used to identify cases of autism and related pervasive developmental disorders at 18 months of age. It is emphasized that the CHAT is not a diagnostic instrument but can identify potential cases of autism spectrum disorders for a full diagnostic assessment.
Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase

ABSTRACT The antiviral activity of a new series of thymidine analogs was determined against vaccinia virus (VV), cowpox virus (CV), herpes simplex virus, and varicella-zoster virus. Several compounds were identified that had good activity against each of the viruses, including a set of novel 5-substituted deoxyuridine analogs. To investigate the possibility that these drugs might be phosphorylated preferentially by the viral thymidine kinase (TK) homologs, the antiviral activities of these compounds were also assessed using TK-deficient strains of some of these viruses. Some of these compounds were shown to be much less effective in the absence of a functional TK gene in CV, which was unexpected given the high degree of amino acid identity between this enzyme and its cellular homolog. This unanticipated result suggested that the CV TK was important in the mechanism of action of these compounds and also that it might phosphorylate a wider variety of substrates than other type II enzymes. To confirm these data, we expressed the VV TK and human TK1 in bacteria and isolated the purified enzymes. Enzymatic assays demonstrated that the viral TK could efficiently phosphorylate many of these compounds, whereas most of the compounds were very poor substrates for the cellular kinase, TK1. Thus, the specific phosphorylation of these compounds by the viral kinase may be sufficient to explain the TK dependence. This unexpected result suggests that selective phosphorylation by the viral kinase may be a promising new approach in the discovery of highly selective inhibitors of orthopoxvirus replication.
Antisense approaches in prostate cancer

Patients with hormone refractory prostate cancer have limited treatment options and new therapies are urgently needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets that are involved in apoptosis, growth factors, cell signalling and the androgen receptor (AR). Antisense oligonucleotides are short sequences of synthetic modified DNA that are designed to be complimentary to a selected gene’s mRNA and thereby specifically inhibit expression of that gene. The antisense approach continues to hold promise as a therapeutic modality to target genes involved in cancer progression, especially those in which the gene products are not amenable to small molecule inhibition or antibodies. The current status and future direction of a number of antisense oligonucleotides targeting several genes, including BCL-2, BCL-XL, clusterin, the inhibitors of apoptosis (IAP) family, MDM2, protein kinase C-alpha, c-raf, insulin-like growth factor binding proteins and the AR, that have potential clinical use in prostate cancer are reviewed.
Biochemical and Metabolic Changes in Arsenic Contaminated Boehmeria nivea L.

Arsenic (As) is identified by the EPA as the third highest toxic inorganic contaminant. Almost every 9th or 10th human in more than 70 countries including mainland China is affected by As. Arsenic along with other toxins not only affects human life but also creates alarming situations such as the deterioration of farm lands and desertion of industrial/mining lands. Researchers and administrators have agreed to opt for phytoremediation of As over costly cleanups. Boehmeria nivea L. can soak up various heavy metals, such as Sb, Cd, Pb, and Zn. But the effect of As pollution on the biology and metabolism of B. nivea has been somewhat overlooked. This study attempts to evaluate the extent of As resistance, chlorophyll content, and metabolic changes in As-polluted (5, 10, 15, and 20 mg L−1 As) B. nivea in hydroponics. Toxic effects of As in the form of inhibited growth were apparent at the highest level of added As. The significant changes in the chlorophyll, electrolyte leakage, and H2O2, significant increases in As in plant parts, catalase (CAT), and malondialdehyde (MDA), with applied As revealed the potential of B. nivea for As decontamination. By employing the metabolic machinery of B. nivea, As was sustainably removed from the contaminated areas.
Molecular Dissection of the Mechanisms of Substrate Recognition and F-actin-mediated Activation of Cofilin-phosphatase Slingshot-1*

Slingshot-1 (SSH1), a member of a dual-specificity protein phosphatase family, regulates actin dynamics by dephosphorylating and reactivating cofilin, an actin-depolymerizing factor. SSH1 has the SSH family-specific, N-terminal, noncatalytic (SSH-N) domain, consisting of the A and B subdomains. SSH1 is activated by binding to actin filaments. In this study, we examined the mechanisms of SSH1 substrate recognition of phosphocofilin (P-cofilin) and SSH1 activation by F-actin. We found that P-cofilin binds to a phosphatase-inactive mutant, SSH1(CS), in which the catalytic Cys-393 is replaced by Ser. Using a series of deletion mutants, we provided evidence that both the phosphatase (P) domain and the adjacent B domain are indispensable for P-cofilin binding of SSH1(CS) and cofilin-phosphatase activity of SSH1. In contrast, the A domain is required for the F-actin-mediated activation of SSH1, but not for P-cofilin binding or basal cofilin-phosphatase activity. The P domain alone is sufficient for the phosphatase activity toward p-nitrophenyl phosphate (pNPP), indicating that the SSH-N domain is not essential for the basal phosphatase activity of SSH1. Addition of F-actin increased the cofilin-phosphatase activity of SSH1 more than 1200-fold, but the pNPP-phosphatase activity only 2.2-fold, which suggests that F-actin principally affects the cofilin-specific phosphatase activity of SSH1. When expressed in cultured cells, SSH1, but not its mutant deleted of SSH-N, accumulated in the rear of the lamellipodium. Together, these findings suggest that the conserved SSH-N domain plays critical roles in P-cofilin recognition, F-actin-mediated activation, and subcellular localization of SSH1.
Analyses of renal outcome following transplantation adjusting for informative right censoring and demographic factors: A longitudinal study

Demographic factors such as race, vital status, gender, and age could affect the final renal outcome of patients who undergo renal transplantation. These demographic factors could be assessed at the recipient and donor levels. Repeated measures for blood urea nitrogen (BUN) are typically recorded for each patient following renal transplantation, as a biomarker to assess renal progress. However, once a patient develops renal failure due to graft rejection, no measurement of BUN can be registered and the patient goes back to dialysis. This causes loss of follow-up and incomplete data on BUN measurements, a problem referred to as informative right censoring. If this problem is ignored, inaccurate, and biased estimates will be generated. In this study, unbiased estimates for the rate of change of BUN levels over time adjusted for informative right censoring and demographic factors were acquired using a sophisticated model of analysis. Our results demonstrated that BUN levels for Caucasians were decreasing at a greater rate than African Americans (p < 0.0001). When donors are deceased, African American recipients showed an increase instead of a decrease in their BUN levels following transplantation. Moreover, African Americans showed a decrease in their BUN levels when the donors were African Americans compared with when donors were Caucasians (p = 0.03). Our results also showed that BUN levels were decreasing at a greater rate when donors and recipients were of different gender than when they were of the same gender (p = 0.009). These results suggest that the success of renal transplantation is impacted by the donor/recipient demographic factors.
Exon capture phylogenomics: efficacy across scales of divergence

The evolutionary histories of species are not measured directly, but estimated using genealogies inferred for particular loci. Individual loci can have discordant histories, but in general we expect to infer evolutionary histories more accurately as more of the genome is sampled. High Throughput Sequencing (HTS) is now providing opportunities to incorporate thousands of loci in ‘phylogenomic’ studies. Here, we used target enrichment to sequence c.3000 protein‐coding exons in a group of Australian skink lizards (crown group age c.80 Ma). This method uses synthetic probes to ‘capture’ target exons that were identified in the transcriptomes of selected probe design (PD) samples. The target exons are then enriched in sample DNA libraries prior to performing HTS. Our main goal was to study the efficacy of enrichment of targeted loci at different levels of phylogenetic divergence from the PD species. In taxa sharing a common ancestor with PD samples up to c.20 Ma, we detected little reduction in efficacy, measured here as sequencing depth of coverage. However, at around 80 Myr divergence from the PD species, we observed an approximately two‐fold reduction in efficacy. A secondary goal was to develop a workflow for analysing exon capture studies of phylogenetically diverse samples, while minimizing potential bias. Our approach assembles each exon in each sample separately, by first recruiting short sequencing reads having homology to the corresponding protein sequence. In sum, custom exon capture provides a complement to existing, more generic target capture methods and is a practical and robust option across low‐moderate levels of phylogenetic divergence.
Empowerment and social work research - participatory action research and the relationship between the extent of mental health consumers' involvement in research and its capacity to serve an empowering function

A review of research specific to the active participation of mental health consumers in mental health research indicates that consumers have little input into mental health services program development or evaluation. Participatory action research, which is strengths-based and action-oriented, offers a process through which people utilizing mental health services and social work researchers can work together to develop evaluation and assessment tools that are both more relevant to program outcomes and empowering to the people whose progress they measure. Congruent with basic social work values of empowerment and social justice, participatory research assists in breaking down long-standing power imbalances between consumers and workers / researchers in the field of mental health. The primary intervention involved the practicum student working collaboratively with a group of mental health consumers to design and complete a research project, where the topic was chosen by the consumer researchers. The student prepared educational sessions so that knowledge of the research process was transferred to the consumer researchers. The consumer researchers progressed through each phase of the project, ultimately completing the project and publishing the research findings. The practicum student learned how to facilitate a participatory action research project, as well as learning the skills associated with working with self-help organizations and their members. Learning goals included increased proficiency in project management skills, research management skills, and research team coordination. Facilitation of a participatory action research project differs from others in its emphasis on shared decision-making and ongoing examination of power relationships.
A Platform for Partnership: A Technology Review of the Padlet sharing platform.

Since technology permeates every aspect of contemporary life, just navigating Higher Education (HE) in the 21 st century makes you, to an extent, ‘tech savvy’. However, when looking to technology to assist student/staff partnerships, colleagues need to take their practice beyond Microsoft Office, social media and Photoshop. During a student/staff partnership research project, a student and a higher education professional used the online platform Padlet as their selected medium for collaboration, in order to replicate such of Healy’s principles of partnership as inclusivity, reciprocity, trust and community (Healy et al ., 2014).
Regional unemployment and employee loyalty: evidence from 12 UK regions

ABSTRACT This study investigates the relationship between unemployment and employee loyalty across UK regions. It is argued that higher regional unemployment depresses wages and increases the cost of a potential job loss, thus providing an incentive for employees to be loyal to their employer. Using data from the Work and Employment Relations Survey (WERS), the results confirm the positive association between regional unemployment and employee loyalty. A disaggregated analysis by type of business reveals that this association is stronger in the private sector. The study adds a spatial dimension to an emergent literature that examines how unemployment affects the employed.
Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2.

BACKGROUND & AIMS Diarrhea results from reduced net fluid and salt absorption caused by an imbalance in intestinal absorption and secretion. The bulk of sodium and water absorption in the intestine is mediated by Na(+)/H(+) exchanger 3 (NHE3), located in the luminal membrane of enterocytes. We investigated the effect of lysophosphatidic acid (LPA) on Na(+)/H(+) exchanger activity and Na(+)-dependent fluid absorption in the intestine. METHODS We analyzed the effects of LPA on fluid absorption in intestines of wild-type mice and mice deficient in Na(+)/H(+) exchanger regulatory factor 2 (NHERF2; Nherf2(-/-)) or LPA(2) (Lpa(2)(-/-)). Roles of LPA(5) and NHERF2 were determined by analysis of heterologous expression. RESULTS Under basal conditions, LPA increased fluid absorption in an NHE3-dependent manner and restored the net fluid loss in a mouse model of acute diarrhea. Expression of the LPA receptor LPA(5) was necessary for LPA-induced stimulation of NHE3 activity in colonic epithelial cells. Stimulation of NHE3 by the LPA-LPA(5) signaling required coexpression of NHERF2, which interacted with LPA(5). LPA-mediated intestinal fluid absorption was impaired in Nherf2(-/-) mice, demonstrating the requirement for NHERF2 in LPA(5) activity. However, fluid absorption was unaltered in Lpa(2)(-/-) mice. LPA stimulated NHE3 and fluid absorption in part by increasing NHE3 protein abundance at the brush border membrane of intestinal epithelial cells. CONCLUSIONS LPA is a potent stimulant of NHE3 and fluid absorption in the intestine, signaling through LPA(5). Regulation by LPA(5) depends on its interaction with NHERF2. LPA might be useful in the treatment of certain diarrheal diseases.
Trends in the Types of Usual Sources of Care: A Shift from People to Places or Nothing at All.

OBJECTIVE (1) To examine usual source of care (USC) trends across four categories (No USC, Person USC, Person, in Facility USC, and Facility USC), and (2) to determine whether USC types are associated with emergency department (ED) visits and hospital admissions. DATA SOURCE 1996-2014 Medical Expenditure Panel Surveys. STUDY DESIGN We stratified each USC category, by age, region, gender, poverty, insurance, race/ethnicity, and education and used regression to determine the characteristics associated with USC types, ED visits, and hospital admissions. PRINCIPAL FINDINGS Those with No USC and Facility USCs increased 10 and 18 percent, respectively, while those with Person USCs decreased by 43 percent. Compared to those in the lowest income bracket, those in the highest income bracket were less likely to have a Facility USC. Among those with low incomes, individuals with No USC, Person, in Facility, and Facility USCs were more likely to have ED visits than those with Person USCs. CONCLUSIONS A growing number are reporting facilities as their USCs or none at all. The impact of these trends is uncertain, although we found that some USC types are associated with ED visits and hospital admissions. Tracking USCs will be crucial to measuring progress toward enhanced care efficiency.
Exhaled nitric oxide: Interactions between asthma, hayfever, and atopic dermatitis in school children

Clinicians frequently rely on reported symptoms and basic pulmonary function testing to assess asthma prevalence in the community. However, given that spirometry results are often normal for asthmatic children and the fact that there is no equivalent word for ‘wheeze’ in languages other than English, the assessment of asthma prevalence can be troublesome.
Notch1 regulates chemotaxis and proliferation by controlling the CC‐chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia

Tumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T‐ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand‐independent signalling and/or prolonging Notch1 half‐life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ‐Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine receptors. Our results indicate that γ‐Secretase inhibitor negatively regulates the transcription level of the CC chemokine receptors 5 and 9 in T‐ALL cell lines and patients' primary leukaemia cells, leaving CXCR4 expression unaltered. The Notch pathway also controls CCR5‐ and CCR9‐mediated biological effects, ie chemotaxis and proliferation. Furthermore, engaging CCR9 through CCL25 administration rescues proliferation inhibition associated with abrogation of Notch activity. Finally, through RNA interference we demonstrated that the oncogenic isoform in T‐ALL, Notch1, plays a role in controlling CCR5 and CCR9 expression and functions. These findings suggest that Notch1, acting in concert with chemokine receptors pathways, may provide leukaemia cells with proliferative advantage and specific chemotactic abilities, therefore influencing tumour cell progression and localization. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Restorative Activities of Community-Dwelling Elders

This study was conducted to identify the restorative activities of community-dwelling elders. Exposure to restorative activities, such as observing nature, is associated with improved concentration, more effective cognitive functioning, and feelings of greater mental energy, peacefulness, and refreshment. Little literature exists regarding the types and benefits of restorative activities engaged in by elders, a group in need of means to promote optimal daily functioning. A qualitative descriptive design was used. Thirty (28 women, 2 men) community-dwelling elders (ages 65 to 92 years) were interviewed using open-ended questions to ascertain their perceptions of restorative activities. A content analysis of themes produced 12 categories of restorative activities: creative outlets, altruism, nature, social connections, cognitive challenges, physical activity, reading, family connections, spirituality and reflection, cultural activities, travel, and other activities. Additional studies with larger, culturally diverse samples and more men are warranted before implementing restorative interventions with elders in the hopes of promoting optimal functioning and well-being.