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Students often find learning and applying theory difficult and potentially disconnected from practice. Using theory to guide occupational therapy assessment and intervention preserves the distinct value of occupational therapy. One way students develop professional reasoning is by learning how to use theory. Theoretical knowledge guides the professional reasoning questions that students and practitioners seek to answer. Teaching occupational therapy theory needs to involve clear, engaging, and meaningful activities that foster an explicit focus on occupation. This paper presents an innovative way of teaching theory in occupational therapy. We explain a thinking cap analogy to organize the theoretical knowledge that guides professional reasoning. This analogy involves the instructor wearing a hat as a thinking cap to represent an occupation-centered model of practice on which objects (frames of reference) can be added as flair. We describe the thinking cap analogy in detail and how this analogy builds on Ikiugu's framework for combining theoretical conceptual models. Multiple years of student course feedback demonstrate the usefulness of this analogy as a teaching innovation. This method for teaching theory can advance how students use theoretical knowledge to guide professional reasoning in practice and value occupation, performance, and participation as central to occupational therapy.

Abstract Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p

Summary: Background: Tumour-infiltrating lymphocytes (TILs) are crucial for effective immune checkpoint blockade (ICB) therapy in solid tumours. However, ∼70% of these tumours exhibit poor lymphocyte infiltration, rendering ICB therapies less effective. Methods: We developed a bioinformatics pipeline integrating multiple previously unconsidered factors or datasets, including tumour cell immune-related pathways, copy number variation (CNV), and single tumour cell sequencing data, as well as tumour mRNA-seq data and patient survival data, to identify targets that can potentially improve T cell infiltration and enhance ICB efficacy. Furthermore, we conducted wet-lab experiments and successfully validated one of the top-identified genes. Findings: We applied this pipeline in solid tumours of the Cancer Genome Atlas (TCGA) and identified a set of genes in 18 cancer types that might potentially improve lymphocyte infiltration and ICB efficacy, providing a valuable drug target resource to be further explored. Importantly, we experimentally validated SUN1, which had not been linked to T cell infiltration and ICB therapy previously, but was one of the top-identified gene targets among 3 cancer types based on the pipeline, in a mouse colon cancer syngeneic model. We showed that Sun1 KO could significantly enhance antigen presentation, increase T-cell infiltration, and improve anti-PD1 treatment efficacy. Moreover, with a single-cell multiome analysis, we identified subgene regulatory networks (sub-GRNs) showing Stat proteins play important roles in enhancing the immune-related pathways in Sun1-KO cancer cells. Interpretation: This study not only established a computational pipeline for discovering new gene targets and signalling pathways in cancer cells that block T-cell infiltration, but also provided a gene target pool for further exploration in improving lymphocyte infiltration and ICB efficacy in solid tumours. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Abstract The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP’s potential as a novel therapeutic target.

Abstract Background Cells orchestrate histone biogenesis with strict temporal and quantitative control. To efficiently regulate histone biogenesis, the repetitive Drosophila melanogaster replication-dependent histone genes are arrayed and clustered at a single locus. Regulatory factors concentrate in a nuclear body known as the histone locus body (HLB), which forms around the locus. Historically, HLB factors are largely discovered by chance, and few are known to interact directly with DNA. It is therefore unclear how the histone genes are specifically targeted for unique and coordinated regulation. Results To expand the list of known HLB factors, we performed a candidate-based screen by mapping 30 publicly available ChIP datasets of 27 unique factors to the Drosophila histone gene array. We identified novel transcription factor candidates, including the Drosophila Hox proteins Ultrabithorax (Ubx), Abdominal-A (Abd-A), and Abdominal-B (Abd-B), suggesting a new pathway for these factors in influencing body plan morphogenesis. Additionally, we identified six other factors that target the histone gene array: JIL-1, hormone-like receptor 78 (Hr78), the long isoform of female sterile homeotic (1) (fs(1)h) as well as the general transcription factors TBP associated factor 1 (TAF-1), Transcription Factor IIB (TFIIB), and Transcription Factor IIF (TFIIF). Conclusions Our foundational screen provides several candidates for future studies into factors that may influence histone biogenesis. Further, our study emphasizes the powerful reservoir of publicly available datasets, which can be mined as a primary screening technique.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic highlighted the importance of vaccine innovation in public health. Hundreds of vaccines built on numerous technology platforms have been rapidly developed against SARS-CoV-2 since 2020. Like all vaccine platforms, an important bottleneck to viral-vectored vaccine development is manufacturing. Here, we describe a scalable manufacturing protocol for replication-competent SARS-CoV-2 Spike-pseudotyped vesicular stomatitis virus (S-VSV)–vectored vaccines using Vero cells grown on microcarriers in a stirred-tank bioreactor. Using Cytodex 1 microcarriers over 6 days of fed-batch culture, Vero cells grew to a density of 3.95 ± 0.42 ×106 cells/mL in 1-L stirred-tank bioreactors. Ancestral strain S-VSV reached a peak titer of 2.05 ± 0.58 ×108 plaque-forming units (PFUs)/mL at 3 days postinfection. When compared to growth in plate-based cultures, this was a 29-fold increase in virus production, meaning a 1-L bioreactor produces the same amount of virus as 1,284 plates of 15 cm. In addition, the omicron BA.1 S-VSV reached a peak titer of 5.58 ± 0.35 × 106 PFU/mL. Quality control testing showed plate- and bioreactor-produced S-VSV had similar particle-to-PFU ratios and elicited comparable levels of neutralizing antibodies in immunized hamsters. This method should enhance preclinical and clinical development of pseudotyped VSV-vectored vaccines in future pandemics.

Recent cell and animal studies suggest the potential of blackcurrants (BCs; Ribes nigrum) as a dietary agent that may reduce the risk of cardiovascular disease (CVD) by improving dyslipidemia, oxidative stress, and inflammation. This study aimed to examine the effects of BC anthocyanin (ACN) extract supplementation on biomarkers of CVD risk in healthy adult women in menopause transition. The effects of BC ACN supplementation on body composition, fasting blood lipids and biomarkers of inflammation and oxidative stress were evaluated using anthropometric measures and blood samples collected from a pilot randomized controlled clinical trial in peri- and early postmenopausal women. Thirty-eight eligible peri- and early postmenopausal women aged 45–60 completed the entire trial, in which they were randomly assigned into one of three treatment groups: placebo (control group), 392 mg/day (low BC group), or 784 mg/day (high BC group) for six months. The significance of differences in outcomes was tested using repeated-measures ANOVA. Overall, following six-month BC consumption, significantly decreased triglyceride (TG) levels were observed between treatment groups (p < 0.05) in a dose-dependent manner. Plasma interleukin-1β (IL-1β) was significantly reduced in a dose and time dependent manner (p < 0.05). Significant decreases in thiobarbituric acid reactive substances (TBARS) levels were also observed between treatment groups (p < 0.05) in a dose-dependent manner. Six-month change in oxidized LDL was inversely correlated with changes in catalase (CAT) and total antioxidant capacity (TAC) (p < 0.05), while C-reactive protein (hs-CRP) change was positively correlated with changes in TG and IL-1β (p < 0.01). Together, these findings suggest that daily BC consumption for six months effectively improved dyslipidemia, inflammation, and lipid peroxidation, thus potentially mitigating the risk of postmenopausal CVD development in study participants. Future studies with larger sample sizes and at-risk populations are warranted to confirm these findings.

Our aim was to identify proteins that reflect an acute systemic response to prolonged hyperbaric stress and discover potential biomarker pathways for pulmonary O2 toxicity. The study was a double-blind, randomized, crossover design in trained male Navy diver subjects. Each subject completed two dry resting hyperbaric chamber dives separated by a minimum of one week. One dive exposed the subject to 6.5 h of 100% oxygen (O2) at 2ATA. The alternate dive exposed the subjects to an enhanced air nitrox mixture (EAN) containing 30.6% O2 at the same depth for the same duration. Venous blood samples collected before (PRE) and after (POST) each dive were prepared and submitted to LC-MS/MS analysis (2 h runs). A total of 346 total proteins were detected and analyzed. A total of 12 proteins were significantly increased at EANPOST (vs. EANPRE), including proteins in hemostasis and immune signaling and activation. Significantly increased proteins at O2PRE (vs. O2POST) included neural cell adhesion molecule 1, glycoprotein Ib, catalase, hemoglobin subunit beta, fibulin-like proteins, and complement proteins. EANPOST and O2POST differed in biomarkers related to coagulation, immune signaling and activation, and metabolism. Of particular interest is (EANPOST vs. O2POST), which is protective against oxidative stress.

Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that other immune cell subsets, particularly tissue-resident innate lymphoid cells (ILCs), may benefit from immunotherapy treatment. Here, we describe the recent findings showing immune checkpoint expression on tissue-resident and tumor-infiltrating ILCs and how their effector function is modulated by checkpoint blockade-based therapies in cancer. We discuss the therapeutic potential of ILCs beyond the classical PD-1 and CTLA-4 regulatory molecules, exploring other possibilities to manipulate ILC effector function to further impede tumor growth and quench disease progression.

Conjunctivitis is a common pediatric problem and is broadly divided into infectious and non-infectious etiologies. Bacterial conjunctivitis makes up the majority of cases in children and often presents with purulent discharge and mattering of the eyelids. Treatment is supportive with an individual approach to antibiotic use in uncomplicated cases since it may shorten symptom duration, but is not without risks. Viral conjunctivitis is the other infectious cause and is primarily caused by adenovirus, with a burning, gritty feeling and watery discharge. Treatment is supportive. Allergic conjunctivitis is largely seasonal and presents with bilateral itching and watery discharge. Treatment can include topical lubricants, topical antihistamine agents, or systemic antihistamines. Other causes of conjunctivitis include foreign bodies and non-allergic environmental causes. Contact lens wearers should always be treated for bacterial conjunctivitis and referred to evaluate for corneal ulcers. Neonatal conjunctivitis requires special care with unique pathogens and considerations. This review covers essential information for the primary care pediatric provider as they assess cases of conjunctivitis.

Tumoral calcinosis involves focal calcium deposits in the soft tissues surrounding a joint and most commonly occurs in the hips and elbows, rarely in the cervical spine. Furthermore, it has not been known to be associated with pathologic fractures. To the best of our knowledge, our case report highlights the first case of a pathologic type II odontoid fracture associated with adjacent tumoral calcinosis, resulting in pain, dysphagia, and severe spinal stenosis. The patient underwent a posterior occipitocervical fusion and C1 laminectomy, along with planned tracheostomy and gastrostomy to avoid expected difficulty with postoperative extubation and dysphagia. Additionally, we present a review of existing literature on tumoral calcinosis in the upper cervical spine.