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Impulsivity has been linked to academic performance in the context of Attention Deficit Hyperactivity Disorder, though its influence on a wider spectrum of students remains largely unexplored, particularly in the context of STEM learning (i.e. science, technology, engineering, and math). STEM learning was hypothesized to be more challenging for impulsive students, since it requires the practice and repetition of tasks as well as concerted attention to task performance. Impulsivity was assessed in a cross-sectional sample of 2,476 students in grades 6-12. Results show impulsivity affects a larger population of students, not limited to students with learning disabilities. Impulsivity was associated with lower sources of self-efficacy for science (SSSE), interest in most STEM domains (particularly math), and self-reported STEM skills. The large negative effect size observed for impulsivity was opposed by higher mindset, which describes a student's belief in the importance of effort when learning is difficult. Mindset had a large positive effect size associated with greater SSSE, STEM interest, and STEM skills. When modeled together, results offer that mindset interventions may benefit impulsive students who struggle with STEM. Together, these data suggest important interconnected roles for impulsivity and mindset that can influence secondary students' STEM trajectories.

WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.

Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/β-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/β-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was down-regulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active β-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/β-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/β-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.

Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq) to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.

BACKGROUND: Access to HIV testing and subsequent care among health care workers (HCWs) form a critical component of TB infection control measures for HCWs. Challenges to and gaps in access to HIV services among HCWs may thus compromise TB infection control. This study assessed HCWs HIV and TB screening uptake and explored their preferences for provision of HIV and TB care. METHODS: A cross-sectional mixed-methods study involving 499 HCWs and 8 focus group discussions was conducted in Mukono and Wakiso districts in Uganda between October 2010 and February 2011. RESULTS: Overall, 5% of the HCWs reported a history of TB in the past five years. None reported routine screening for TB disease or infection, although 89% were willing to participate in a TB screening program, 77% at the workplace. By contrast, 95% had previously tested for HIV; 34% outside their workplace, and 27% self-tested. Nearly half (45%) would prefer to receive HIV care outside their workplace. Hypothetical willingness to disclose HIV positive status to supervisors was moderate (63%) compared to willingness to disclose to sexual partners (94%). Older workers were more willing to disclose to a supervisor (adjusted prevalence ratio [APR] = 1.51, CI = 1.16-1.95). Being female (APR = 0.78, CI = 0.68-0.91), and working in the private sector (APR = 0.81, CI = 0.65-1.00) were independent predictors of unwillingness to disclose a positive HIV status to a supervisor. HCWs preferred having integrated occupational services, versus stand-alone HIV care. CONCLUSIONS: Discomfort with disclosure of HIV status to supervisors suggests that universal TB infection control measures that benefit all HCWs are more feasible than distinctions by HIVstatus, particularly for women, private sector, and younger HCWs. However, interventions to reduce stigma and ensuring confidentiality are also essential to ensure uptake of comprehensive HIV care including Isoniazid Preventive Therapy among HCWs.

Lysosomal enzymes function optimally in acidic environments, and elevation of lysosomal pH can impede their ability to degrade material delivered to lysosomes through autophagy or phagocytosis. We hypothesize that abnormal lysosomal pH is a key aspect in diseases of accumulation and that restoring lysosomal pH will improve cell function. The propensity of nanoparticles to end up in the lysosome makes them an ideal method of delivering drugs to lysosomes. This study asked whether acidic nanoparticles could traffic to lysosomes, lower lysosomal pH and enhance lysosomal degradation by the cultured human retinal pigmented epithelial cell line ARPE-19. Acidic nanoparticles composed of poly (DL-lactide-co-glycolide) (PLGA) 502 H, PLGA 503 H and poly (DL-lactide) (PLA) colocalized to lysosomes of ARPE-19 cells within 60 min. PLGA 503 H and PLA lowered lysosomal pH in cells compromised by the alkalinizing agent chloroquine when measured 1 hr. after treatment, with acidification still observed 12 days later. PLA enhanced binding of Bodipy-pepstatin-A to the active site of cathepsin D in compromised cells. PLA also reduced the cellular levels of opsin and the lipofuscin-like autofluorescence associated with photoreceptor outer segments. These observations suggest the acidification produced by the nanoparticles was functionally effective. In summary, acid nanoparticles lead to a rapid and sustained lowering of lysosomal pH and improved degradative activity.

A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.

Introduction: Paediatric Critical Care (PCC) supports the recovery of children with severe illness. In the UK, there are 30 PCC units with a total of approximately 400 beds. There is constant demand for these beds with a mean five-day length of stay and admissions increasing at a greater rate than age-specific population growth. Prolonged stay patients account for approximately half of all PCC patient bed days. Children with complex critical illness (CCI) need input from multiple different teams alongside support for their family. CCI often become prolonged PCC-stay patients too. Internationally, there is variation in the definition of CCI, this creates service variation and tensions around what resources can be provided including discharge planning, provision, and support. Objective: The face of Paediatric Critical Care, in the UK and internationally has changed over the last ten years with a growing cohort of complex critically ill patients. This systematic review aims to look at current nomenclature, criteria, and outcome measures of priority in this undefined patient population., Methods and Materials: Inclusion criteria: All types of studies examining children with complex critical illness (age <18 years) admitted to any paediatric critical care. The review is registered on Prospero. Medline, Embase, Maternity and Infant care, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Trip database will be searched from 2014 to May 2024. The search was limited to ten years as children with complex critical illness are a relatively new concept within PCC. Therefore, the timeline was limited to increase the accuracy and applicability of the review. Search limits included all languages, excluded the setting of neonatal intensive care, and age>18 years old. The final search strategy was developed in Medline and peer-reviewed by a health research librarian not involved in the study. This was translated to other databases as appropriate. Four independent reviewers will screen citations for eligible studies and perform data extraction., Discussion: A systematic review methodology has been used to develop a broad understanding of the literature which will be used to develop further work in this area. Using a rigorous and stepwise approach, the whole spectrum of scientific publications on children with complex critical illness in paediatric intensive care will be reviewed, ensuring this study is as comprehensive as possible. This includes quantitative, qualitative, theoretical, and grey literature. A limitation of this systematic review is the use of many terms to describe children with complex critical illness in the literature resulting in a high number of publications on this topic., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Cuevas-Asturias et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Teachers are an important occupational group to consider when addressing vaccine confidence and uptake for school-aged children due to their proximate role within school-based immunization programs. The objectives of this study were to characterize and identify sociodemographic factors associated with vaccine confidence and describe teachers' knowledge of and perceived role in the school-based immunization program, with the aim of informing public health policy and identifying opportunities for supporting teachers in their role in school-based immunization programs., Methods: A cross-sectional survey of elementary and secondary public-school teachers in British Columbia was completed from August to November 2020. Respondents provided sociodemographic information, as well as past vaccination experience, vaccine knowledge, and perceived role in the school-based immunization program. Vaccine confidence was measured using the Vaccine Hesitancy Scale (VHS). Characteristics associated with the VHS sub-scales 'lack of confidence in vaccines' and 'perceived risk of vaccines', were explored using ANOVA. Descriptive analysis was completed for teachers' perceived role in the immunization program., Results: 5,095 surveys were included in this analysis. Overall vaccine confidence was high, with vaccine hesitancy being related to the perceived risk of vaccines rather than a lack of confidence in the effectiveness of vaccines. ANOVA found significant differences for both VHS-sub-scales based on sociodemographic factors, however, the strength of the association was generally small. High general vaccine knowledge and never having delayed or refused a vaccine in the past were associated with higher vaccine confidence. Overall, teachers reported a lack of clarity in their role within the school-based immunization program., Conclusions: This large population-based observational study of teachers highlights a number of key engagement opportunities between public health and the education sector. Using a validated scale, we found that overall, teachers are highly accepting of vaccines, and well situated as potential partners with public health to address vaccine hesitancy., Competing Interests: MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. MS is supported via salary awards from the BC Children’s Hospital Foundation, the Canadian Child Health Clinician Scientist Program and the Michael Smith Foundation for Health Research. HM has been a co-investigator on projects funded by GlaxoSmithKline, Moderna, Pfizer, Sanofi-Pasteur. CSR is funded by a fellowship from the Michael Smith Foundation for Health Research. RD has received fellowships from the Michael Smith Foundation for Health Research and the Canadian Immunization Research Network. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors have declared that no competing interests exist., (Copyright: © 2023 Racey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The production of lignocellulosic-derived biofuels is a highly promising source of alternative energy, but it has been constrained by the lack of a microbial platform capable to efficiently degrade this recalcitrant material and cope with by-products that can be toxic to cells. Species that naturally grow in environments where carbon is mainly available as lignin are promising for finding new ways of removing the lignin that protects cellulose for improved conversion of lignin to fuel precursors. Enterobacter lignolyticus SCF1 is a facultative anaerobic Gammaproteobacteria isolated from tropical rain forest soil collected in El Yunque forest, Puerto Rico under anoxic growth conditions with lignin as sole carbon source. Whole transcriptome analysis of SCF1 during E.lignolyticus SCF1 lignin degradation was conducted on cells grown in the presence (0.1%, w/w) and the absence of lignin, where samples were taken at three different times during growth, beginning of exponential phase, mid-exponential phase and beginning of stationary phase. Lignin-amended cultures achieved twice the cell biomass as unamended cultures over three days, and in this time degraded 60% of lignin. Transcripts in early exponential phase reflected this accelerated growth. A complement of laccases, aryl-alcohol dehydrogenases, and peroxidases were most up-regulated in lignin amended conditions in mid-exponential and early stationary phases compared to unamended growth. The association of hydrogen production by way of the formate hydrogenlyase complex with lignin degradation suggests a possible value added to lignin degradation in the future.

Scientists are increasing their efforts to promote public engagement with their science, but the efficacy of the methods used is often not scientifically evaluated. Here, we designed, installed and evaluated the educational impact of interactive games on touchscreens at two primate research centres based in zoo environments. The games were designed to promote interest in and understanding of primates and comparative psychology, as a scaffold towards interest in science more generally and with the intention of targeting younger individuals (under 16's). We used systematic observational techniques and questionnaires to assess the impact of the games on zoo visitors. The games facilitated increased interest in psychology and science in zoo visitors, and changed the knowledge of visitors, through demonstration of learning about specific scientific findings nested within the games. The impact of such devices was greatest on younger individuals (under 16's) as they were significantly more likely to engage with the games. On the whole, therefore, this study demonstrates that interactive devices can be successful educational tools, and adds to the growing body of evidence that conducting research on public view in zoos can have a tangible impact on public engagement with science.

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

Primate behavioural and cognitive research is increasingly conducted on direct public view in zoo settings. The potential of such facilities for public engagement with science is often heralded, but evidence of tangible, positive effects on public understanding is rare. Here, the effect of a new zoo-based primate research centre on visitor behaviour, learning and attitudes was assessed using a quasi-experimental design. Zoo visitors approached the primate research centre more often when a scientist was present and working with the primates, and reported greater awareness of primates (including conservation) compared to when the scientist was not present. Visitors also reported greater perceived learning when the scientist was present. Installation of information signage had no main effect on visitor attitudes or learning. Visitors who interacted with the signage, however, demonstrated increased knowledge and understanding when asked about the specific information present on the signs (which was related to the ongoing facial expression research at the research centre). The findings show that primate behaviour research centres on public view can have a demonstrable and beneficial effect on public understanding of science.

Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). A high prevalence of Campylobacter concisus was previously detected in paediatric CD and adult UC. Currently, the prevalence of C. concisus in adult CD and the preferential colonization sites of Campylobacter species in the human intestine are unknown. In this study, we examined the prevalence of Campylobacter species in biopsies collected from multiple anatomic sites of adult patients with IBD and controls., Methods: Three hundred and one biopsies collected from ileum, caecum, descending colon and rectum of 28 patients IBD (15 CD and 13 UC) and 33 controls were studied. Biopsies were used for DNA extraction and detection of Campylobacter species by PCR-sequencing and Campylobacter cultivation., Results: A significantly higher prevalence of C. concisus in colonic biopsies of patients with CD (53%) was detected as compared with the controls (18%). Campylobacter genus-PCR positivity and C. concisus positivity in patients with UC were 85% and 77% respectively, being significantly higher than that in the controls (48% and 36%). C. concisus was more often detected in descending colonic and rectal biopsies from patients with IBD in comparison to the controls. C. concisus was isolated from patients with IBD., Conclusion: The high intestinal prevalence of C. concisus in patients with IBD, particularly in the proximal large intestine, suggests that future studies are needed to investigate the possible involvement of C. concisus in a subgroup of human IBD. To our knowledge, this is the first report of the association between adult CD and C. concisus as well as the first study of the preferential colonization sites of C. concisus in the human intestine.

Campylobacter concisus has garnered increasing attention due to its association with intestinal disease, thus, the pathogenic potential of strains isolated from different intestinal diseases was investigated. A method to isolate C. concisus was developed and the ability of eight strains from chronic and acute intestinal diseases to adhere to and invade intestinal epithelial cells was determined. Features associated with bacterial invasion were investigated using comparative genomic analyses and the effect of C. concisus on host protein expression was examined using proteomics. Our isolation method from intestinal biopsies resulted in the isolation of three C. concisus strains from children with Crohn's disease or chronic gastroenteritis. Four C. concisus strains from patients with chronic intestinal diseases can attach to and invade host cells using mechanisms such as chemoattraction to mucin, aggregation, flagellum-mediated attachment, "membrane ruffling", cell penetration and damage. C. concisus strains isolated from patients with chronic intestinal diseases have significantly higher invasive potential than those from acute intestinal diseases. Investigation of the cause of this increased pathogenic potential revealed a plasmid to be responsible. 78 and 47 proteins were upregulated and downregulated in cells infected with C. concisus, respectively. Functional analysis of these proteins showed that C. concisus infection regulated processes related to interleukin-12 production, proteasome activation and NF-κB activation. Infection with all eight C. concisus strains resulted in host cells producing high levels of interleukin-12, however, only strains capable of invading host cells resulted in interferon-γ production as confirmed by ELISA. These findings considerably support the emergence of C. concisus as an intestinal pathogen, but more significantly, provide novel insights into the host immune response and an explanation for the heterogeneity observed in the outcome of C. concisus infection. Moreover, response to infection with invasive strains has substantial similarities to that observed in the inflamed mucosa of Crohn's disease patients.

Campylobacter concisus is an emerging pathogen of the human gastrointestinal tract. Its role in different diseases remains a subject of debate; this may be due to strain to strain genetic variation. Here, we sequence and analyze the genome of a C. concisus from a biopsy of a child with Crohn's disease (UNSWCD); the second such genome for this species. A 1.8 Mb genome was assembled with paired-end reads from a next-generation sequencer. This genome is smaller than the 2.1 Mb C. concisus reference BAA-1457. While 1593 genes were conserved across UNSWCD and BAA-1457, 138 genes from UNSWCD and 281 from BAA-1457 were unique when compared against the other. To further validate the genome assembly and annotation, comprehensive shotgun proteomics was performed. This confirmed 78% of open reading frames in UNSWCD and, importantly, provided evidence of expression for 217 proteins previously defined as 'hypothetical' in Campylobacter. Substantial functional differences were observed between the UNSWCD and the reference strain. Enrichment analysis revealed differences in membrane proteins, response to stimulus, molecular transport and electron carriers. Synteny maps for the 281 genes not present in UNSWCD identified seven functionally associated gene clusters. These included one associated with the CRISPR family and another which encoded multiple restriction endonucleases; these genes are all involved in resistance to phage attack. Many of the observed differences are consistent with UNSWCD having adapted to greater surface interaction with host cells, as opposed to BAA-1457 which may prefer a free-living environment.