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Background/objectives: Although the use of radiation-sensitizing agents has been shown to enhance the effect of radiation on tumor cells, the blood-brain barrier (BBB) impedes these agents from reaching brain tumor sites when provided systemically. Localized methods of sensitizer delivery, utilizing hydrogels, have the potential to bypass the blood-brain barrier. This study examined the ability of photochemical internalization (PCI) of hydrogel-released bleomycin to enhance the growth-inhibiting effects of radiation on multi-cell glioma spheroids in vitro., Methods: Loaded fibrin hydrogel layers were created by combining thrombin, fibrinogen, and bleomycin (BLM). Supernatants from these layers were collected, combined with photosensitizer, and added to F98 glioma spheroid cultures. Following light (PCI) and radiation treatment, at increasing dosages, spheroid growth was monitored for 14 days., Results: PCI of released BLM significantly reduced the radiation dose required to achieve equivalent efficacy compared to radiation or BLM + RT alone. Both immediate and delayed RT delivery post-BLM-PCI resulted in similar degrees of growth inhibition., Conclusions: Non-degraded BLM was released from the fibrin hydrogel. PCI of BLM synergistically increased the growth-inhibiting effects of radiation treatment compared to radiation and BLM, as well as radiation acting as a single treatment.

Mycobacterium tuberculosis ( Mtb ) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb , therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb -induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

The gut microbiota and short chain fatty acids (SCFA) have been associated with immune regulation and autoimmune diseases. Autoimmune kidney diseases arise from a loss of tolerance to antigens, often with unclear triggers. In this review, we explore the role of the gut microbiome and how disease, diet, and therapy can alter the gut microbiota consortium. Perturbations in the gut microbiota may systemically induce the translocation of microbiota-derived inflammatory molecules such as liposaccharide (LPS) and other toxins by penetrating the gut epithelial barrier. Once in the blood stream, these pro-inflammatory mediators activate immune cells, which release pro-inflammatory molecules, many of which are antigens in autoimmune diseases. The ratio of gut bacteria Bacteroidetes/Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases including lupus nephritis, MPO-ANCA vasculitis, and Goodpasture's syndrome. Therapies that enhance SCFA-producing bacteria in the gut have powerful therapeutic potential. Dietary fiber is fermented by gut bacteria which in turn release SCFAs that protect the gut barrier, as well as modulating immune responses towards a tolerogenic anti-inflammatory state. Herein, we describe where the current field of research is and the strategies to harness the gut microbiome as potential therapy.

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To identify new diagnostic markers, we performed differential gene expression analysis on transcriptome data from MCC and SCLC tumors. Candidate markers included atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2β (TFAP2B) for MCC, as well as carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for SCLC. Immunostaining for CK20, TTF-1, and new candidate markers was performed on 43 MCC and 59 SCLC samples. All three MCC markers were sensitive and specific, with CK20 and ATOH1 staining 43/43 (100%) MCC and 0/59 (0%) SCLC cases and TFAP2B staining 40/43 (93%) MCC and 0/59 (0%) SCLC cases. TTF-1 stained 47/59 (80%) SCLC and 1/43 (2%) MCC cases. CEACAM6 stained 49/59 (83%) SCLC and 0/43 (0%) MCC cases. Combining CEACAM6 and TTF-1 increased SCLC detection sensitivity to 93% and specificity to 98%. These data suggest that ATOH1, TFAP2B, and CEACAM6 should be explored as markers to differentiate MCC and SCLC.

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

Accumulation of 7-ketocholesterol (7KC) occurs in age-related macular degeneration (AMD) and was found previously to promote fibrosis, an untreatable cause of vision loss, partly through induction of endothelial-mesenchymal transition. To address the hypothesis that 7KC causes mesenchymal transition of retinal pigment epithelial cells (RPE), we exposed human primary RPE (hRPE) to 7KC or a control. 7KC-treated hRPE did not manifest increased mesenchymal markers, but instead maintained RPE-specific proteins and exhibited signs of senescence with increased serine phosphorylation of histone H3, serine/threonine phosphorylation of mammalian target of rapamycin (p-mTOR), p16 and p21, β-galactosidase labeling, and reduced LaminB1, suggesting senescence. The cells also developed senescence-associated secretory phenotype (SASP) determined by increased IL-1β, IL-6, and VEGF through mTOR-mediated NF-κB signaling, and reduced barrier integrity that was restored by the mTOR inhibitor, rapamycin. 7KC-induced p21, VEGF, and IL-1β were inhibited by an inhibitor of protein kinase C. The kinase regulates IQGAP1 serine phosphorylation. Furthermore, after 7KC injection and laser-induced injury, mice with an IQGAP1 serine 1441-point mutation had significantly reduced fibrosis compared to littermate control mice. Our results provide evidence that age-related accumulation of 7KC in drusen mediates senescence and SASP in RPE, and IQGAP1 serine phosphorylation is important in causing fibrosis in AMD.

Aggression in children is highly prevalent and can have devastating consequences, yet there is currently no objective method to track its frequency in daily life. This study aims to investigate the use of wearable-sensor-derived physical activity data and machine learning to objectively identify physical-aggressive incidents in children. Participants (n = 39) aged 7 to 16 years, with and without ADHD, wore a waist-worn activity monitor (ActiGraph, GT3X+) for up to one week, three times over 12 months, while demographic, anthropometric, and clinical data were collected. Machine learning techniques, specifically random forest, were used to analyze patterns that identify physical-aggressive incident with 1-min time resolution. A total of 119 aggression episodes, lasting 7.3 ± 13.1 min for a total of 872 1-min epochs including 132 physical aggression epochs, were collected. The model achieved high precision (80.2%), accuracy (82.0%), recall (85.0%), F1 score (82.4%), and area under the curve (89.3%) to distinguish physical aggression epochs. The sensor-derived feature of vector magnitude (faster triaxial acceleration) was the second contributing feature in the model, and significantly distinguished aggression and non-aggression epochs. If validated in larger samples, this model could provide a practical and efficient solution for remotely detecting and managing aggressive incidents in children.

Efforts are underway to improve the accuracy of non-specialist screening for oral cancer (OC) risk, yet better screening will only translate into improved outcomes if at-risk individuals comply with specialist referral. Most individuals from low-resource, minority, and underserved (LRMU) populations fail to complete a specialist referral for OC risk. The goal was to evaluate the impact of a novel approach on specialist referral compliance in individuals with a positive OC risk screening outcome. A total of 60 LRMU subjects who had screened positive for increased OC risk were recruited and given the choice of referral for an in-person (20 subjects) or a telehealth (40 subjects) specialist visit. Referral compliance was tracked weekly over 6 months. Compliance was 30% in the in-person group, and 83% in the telehealth group. Approximately 83-85% of subjects from both groups who had complied with the first specialist referral complied with a second follow-up in-person specialist visit. Overall, 72.5% of subjects who had chosen a remote first specialist visit had entered into the continuum of care by the study end, vs. 25% of individuals in the in-person specialist group. A two-step approach that uses telehealth to overcome barriers may improve specialist referral compliance in LRMU individuals with increased OC risk.

Background: Oral cancers have limited diagnostic tools to aid clinical management. Current evidence indicates that alterations in hemidesmosomes, the adhesion complexes primarily involved in epithelial attachment to the basement membrane, are correlated to cancer phenotype for multiple cancers. This systematic review aimed to assess the experimental evidence for hemidesmosomal alterations, specifically in relation to oral potentially malignant disorders and oral squamous cell carcinomas., Methods: We conducted a systemic review to summarise the available literature on hemidesmosomal components and their role in oral pre-cancer and cancer. Relevant studies were retrieved from a comprehensive search of Scopus, Ovid MEDLINE, Ovid Embase and Web of Science., Results: 26 articles met the inclusion criteria, of which 19 were in vitro studies, 4 in vivo studies, 1 in vitro and in vivo study, and 2 in vitro and cohort studies. Among them, 15 studies discussed individual alpha-6 and/or beta-4 subunits, 12 studies discussed the alpha-6 beta-4 heterodimers, 6 studies discussed the entire hemidesmosome complex, 5 studies discussed bullous pemphigoid-180, 3 studies discussed plectin, 3 studies discussed bullous pemphigoid antigen-1 and 1 study discussed tetraspanin., Conclusion: Heterogeneity in cell type, experimental models, and methods were observed. Alterations in hemidesmosomal components were shown to contribute to oral pre-cancer and cancer. We conclude that there is sufficient evidence for hemidesmosomes and their components to be potential biomarkers for evaluating oral carcinogenesis.

Vouchers that reduce the cost of sport and active recreation participation have been shown to increase children's and adolescent's physical activity levels. Yet, the influence of government-led voucher programs on the capacity of sport and active recreation organisations is unclear. This qualitative study explored the experiences of stakeholders in the sport and recreation sector that were engaged in implementing the New South Wales (NSW) Government's Active Kids voucher program in Australia. Semi-structured interviews were conducted with 29 sport and active recreation providers. Interview transcriptions were analysed by a multidisciplinary team using the Framework method. Overall, participants reported that the Active Kids voucher program was an acceptable intervention to address the cost barrier to participation for children and adolescents. Three main steps influenced the capacity of organisations to deliver their sport and recreation programs and the voucher program: (1) Implementation priming-alignment of the intervention aims with stakeholder priorities and early information sharing, (2) Administrative ease-enhanced technology use and establishment of simple procedures, and (3) Innovation impacts-enablement of staff and volunteers to address barriers to participation for their participants. Future voucher programs should include strategies to enhance the capacity of sport and active recreation organisations to meet program guidelines and increase innovation.

A common herbicide, atrazine, is associated with poor health. Atrazine acts as an endocrine disruptor at supra-environmental levels. Little research, however, has been conducted regarding chronic exposure to environmental atrazine concentrations across generations. This study utilized comprehensive endpoint measures to investigate the effects of chronic exposure to a conservative atrazine concentration (0.02 ng/mL), measured in Australian waterways, on male mice fertility across two generations. Mice were exposed through the maternal line, from the pre-conception period and through the F1 and F2 generations until three or six months of age. Atrazine did not impact sperm function, testicular morphology nor germ cell parameters but did alter the expression of steroidogenic genes in the F1, down-regulating the expression of Cyp17a1 (Cytochrome P450 family 17, subfamily A member 1; p = 0.0008) and Ddx4 (DEAD-box helicase 4; p = 0.007), and up-regulating the expression of Star (Steroidogenic acute regulatory protein; p = 0.017). In the F2, atrazine induced up-regulation in the expression of Star ( p = 0.016). The current study demonstrates that chronic exposure to an environmentally relevant atrazine concentration perturbs testicular steroid-associated gene expression that varies across generations. Future studies through the paternal and combined parental lineages should be undertaken to further elucidate the multigenerational effects of atrazine on male fertility.

Angiotensin II (Ang II), a peptide hormone generated as part of the renin-angiotensin system, has been implicated in the pathophysiology of many cardiovascular diseases such as peripheral artery disease, heart failure, hypertension, coronary artery disease and other conditions. Liraglutide, known as an incretin mimetic, is one of the glucagon-like peptide-1 (GLP-1) receptor agonists, and has been proven to be effective in the treatment of cardiovascular disorders beyond adequate glycemic control. The objective of this review is to compile our recent experimental outcomes-based studies, and provide an overview the cardiovascular protection from liraglutide against Ang II- and pressure overload-mediated deleterious effects on the heart. In particular, the mechanisms of action underlying the inhibition of oxidative stress, vascular endothelial dysfunction, hypertension, cardiac fibrosis, left ventricular hypertrophy and heart failure with liraglutide are addressed. Thus, we support the notion that liraglutide continues to be a useful add-on therapy for the management of cardiovascular diseases.

Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that have integrated into the human genome. Using publicly available RNA-seq data from 63 cervical cancer patients, we investigated the expression of ERVs in cervical cancers. Four aspects of cervical cancer were investigated: patient ancestral background, tumor HPV type, tumor stage and patient survival. Between the racial subgroups, 74 ERVs were significantly differentially expressed, with Black Americans having 30 upregulated and 44 downregulated (including MER21C, HERV9-int, and HERVH-int) ERVs when compared to White Americans. We found that 3313 ERVs were differentially expressed between HPV subgroups, including MER41A, HERVH-int and HERVK9. There were 28 downregulated (including MLT1D and HERVH-int) and 61 upregulated (including MER41A) ERVs in locally advanced-stage compared to early-stage samples. Tissue microarrays of cervical cancer patients were used to investigate the protein expression of ERVs with protein coding potential (i.e., HERVK and ERV3). Significant differences in protein expression of ERV3 ( p = 0.000905) were observed between early-stage and locally advanced-stage tumors. No significant differential expression at the protein level was found for HERVK7 ( p = 0.243). We also investigated a prognostic model, supplementing a baseline prediction model using FIGO stage, age and HPV positivity with ERVs data. The expression levels of all ERVs in the HERVd were input into a Lasso-Cox proportional hazards model, developing a predictive 67-ERV panel. When ERVs expression levels were supplemented with the clinical data, a significant increase in prognostic power ( p = 9.433 × 10 -15 ) relative to that obtained with the clinical parameters alone ( p = 0.06027) was observed. In summary, ERV RNA expression in cervical cancer tumors is significantly different among racial cohorts, HPV subgroups and disease stages. The combination of the expression of certain ERVs in cervical cancers with clinical factors significantly improved prognostication compared to clinical factors alone; therefore, ERVs may serve as future prognostic biomarkers and therapeutic targets. Novelty and Impact: When endogenous retroviral (ERV) expression signatures were combined with currently employed clinical prognosticators of relapse of cervical cancer, the combination outperformed prediction models based on clinical prognosticators alone. ERV expression signatures in tumor biopsies may therefore be useful to help identify patients at greater risk of recurrence. The novel ERV expression signatures or adjacent genes possibly impacted by ERV expression described here may also be targets for the development of future therapeutic interventions.

Late detection and specialist referral result in poor oral cancer outcomes globally. High-risk LRMU populations usually do not have access to oral medicine specialists, a specialty of dentistry, whose expertise includes the identification, treatment, and management of oral cancers. To overcome this access barrier, there is an urgent need for novel, low-cost tele-health approaches to expand specialist access to low-resource, remote and underserved individuals. The goal of this study was to compare the diagnostic accuracy of remote versus in-person specialist visits using a novel, low-cost telehealth platform consisting of a smartphone-based, remote intraoral camera and custom software application. A total of 189 subjects with suspicious oral lesions requiring biopsy (per the standard of care) were recruited and consented. Each subject was examined, and risk factors were recorded twice: once by an on-site specialist, and again by an offsite specialist. A novel, low-cost, smartphone-based intraoral camera paired with a custom software application were utilized to perform synchronous remote video/still imaging and risk factor assessment by the off-site specialist. Biopsies were performed at a later date following specialist recommendations. The study's results indicated that on-site specialist diagnosis showed high sensitivity (94%) and moderate specificity (72%) when compared to histological diagnosis, which did not significantly differ from the accuracy of remote specialist telediagnosis (sensitivity: 95%; specificity: 84%). These preliminary findings suggest that remote specialist visits utilizing a novel, low-cost, smartphone-based telehealth tool may improve specialist access for low-resource, remote and underserved individuals with suspicious oral lesions.

The tumor microenvironment plays a crucial role in both the development and progression of prostate cancer. Furthermore, identifying protein and gene expression differences between different regions is valuable for treatment development. We applied Digital Spatial Profiling multiplex analysis to formalin-fixed paraffin embedded prostatectomy tissue blocks to investigate protein and transcriptome differences between tumor, tumor-adjacent stroma (TAS), CD45+ tumor, and CD45+ TAS tissue. Differential expression of an immunology/oncology protein panel (n = 58) was measured. OX40L and CTLA4 were expressed at higher levels while 22 other proteins, including CD11c, were expressed at lower levels (FDR < 0.2 and p-value < 0.05) in TAS as compared to tumor epithelia. A tissue microarray analysis of 97 patients with 1547 cores found positive correlations between high expression of CD11c and increased time to recurrence in tumor and TAS, and inverse relationships for CTLA4 and OX40L, where higher expression in tumor correlated with lower time to recurrence, but higher time to recurrence in TAS. Spatial transcriptomic analysis using a Cancer Transcriptome Atlas panel (n = 1825 genes) identified 162 genes downregulated and 69 upregulated in TAS versus tumor, 26 downregulated and 6 upregulated in CD45+ TAS versus CD45+ tumor. We utilized CIBERSORTx to estimate the relative immune cell fractions using CD45+ gene expression and found higher average fractions for memory B, naïve B, and T cells in TAS. In summary, the combination of protein expression differences, immune cell fractions, and correlations of protein expression with time to recurrence suggest that closely examining the tumor microenvironment provides valuable data that can improve prognostication and treatment techniques.

Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. Here, we investigated the impact of adipocyte-specific HDAC9 gene deletion on diet-induced obesity in male and female mice. The HDAC9 gene expression was increased in adipose tissues of obese male and female mice and HDAC9 expression correlated positively with body mass index in humans. Interestingly, female, but not male, adipocyte-specific HDAC9 KO mice on HFD exhibited reduced body weight and visceral adipose tissue mass, adipocyte hypertrophy, and improved insulin sensitivity, glucose tolerance and adipogenic differentiation gene expression. Furthermore, adipocyte-specific HDAC9 gene deletion in female mice improved metabolic health as assessed by whole body energy expenditure, oxygen consumption, and adaptive thermogenesis. Mechanistically, compared to female mice, HFD-fed male mice exhibited preferential HDAC9 expression in the stromovascular fraction, which may have offset the impact of adipocyte-specific HDAC9 gene deletion in male mice. These results suggest that HDAC9 expressed in adipocytes is detrimental to obesity in female mice and provides novel evidence of sex-related differences in HDAC9 cellular expression and contribution to obesity-related metabolic disease.

Maternal reinfection of immune women with novel human cytomegalovirus (HCMV) strains acquired during pregnancy can result in symptomatic congenital CMV (cCMV) infection. Novel animal model strategies are needed to explore vaccine-mediated protections against maternal reinfection. To investigate this in the guinea pig cytomegalovirus (GPCMV) model, a strictly in vivo-passaged workpool of a novel strain, the CIDMTR strain (dose, 1 × 10 7 pfu) was used to infect dams that had been challenged in a previous pregnancy with the 22122 strain, following either sham-immunization (vector only) or vaccination with MVA-vectored gB, gH/gL, or pentameric complex (PC) vaccines. Maternal DNAemia cleared by day 21 in the glycoprotein-vaccinated dams, but not in the sham-immunized dams. Mean pup birth weights were 72.85 ± 10.2, 80.0 ± 6.9, 81.4 ± 14.1, and 89.38 ± 8.4 g in sham-immunized, gB, gH/gL, and PC groups, respectively ( p < 0.01 for control v. PC). Pup mortality in the sham-immunized group was 6/12 (50%), but reduced to 3/35 (8.6%) in combined vaccine groups ( p = 0.0048). Vertical CIDMTR transmission occurred in 6/12 pups (50%) in the sham-vaccinated group, compared to 2/34 pups (6%) in the vaccine groups ( p = 0.002). We conclude that guinea pigs immunized with vectored vaccines expressing 22122 strain-specific glycoproteins are protected after a reinfection with a novel, heterologous clinical isolate (CIDMTR) in a second pregnancy.

Endogenous retroviruses (ERVs) are abundant, repetitive elements dispersed across the human genome and are implicated in various diseases. We investigated two potential roles for ERVs in prostate cancer (PCa). First, the PCa of Black Americans (BA) is diagnosed at an earlier median age and at a more advanced stage than the PCa of White Americans (WA). We used publicly available RNA-seq data from tumor-enriched samples of 27 BA and 65 WA PCa patients in order to identify 12 differentially expressed ERVs ( p adj < 0.1) and used a tissue microarray of the PCa cores from an independent set of BA and WA patients to validate the differential protein expression of one of these ERVs, ERV3-1 ( p = 2.829 × 10 -7 ). Second, we used 57 PCa tumors from patients of all ancestries from one hospital as a training set to identify the ERVs associated with time to biochemical relapse. A 29-ERV prognostic panel was then tested and validated on 35 separate PCa tumors from patients obtained in two different hospitals with a dramatic increase in prognostic power relative to clinical parameters alone ( p = 7.4 × 10 -11 ). In summary, ERV RNA expression differences in the prostate tumors of patients of different ancestries may be associated with dissimilarities in the mechanism of cancer progression. In addition, the correlation of expression of certain ERVs in prostate tumors with the risk of biochemical relapse indicates a possible role for ERV expression in cancer progression.

Immune modulation is considered a hallmark of cancer initiation and progression. The recent development of immunotherapies has ushered in a new era of cancer treatment. These therapeutics have led to revolutionary breakthroughs; however, the efficacy of immunotherapy has been modest and is often restricted to a subset of patients. Hence, identification of which cancer patients will benefit from immunotherapy is essential. Multiplex immunofluorescence (mIF) microscopy allows for the assessment and visualization of the tumor immune microenvironment (TIME). The data output following image and machine learning analyses for cell segmenting and phenotyping consists of the following information for each tumor sample: the number of positive cells for each marker and phenotype(s) of interest, number of total cells, percent of positive cells for each marker, and spatial locations for all measured cells. There are many challenges in the analysis of mIF data, including many tissue samples with zero positive cells or "zero-inflated" data, repeated measurements from multiple TMA cores or tissue slides per subject, and spatial analyses to determine the level of clustering and co-localization between the cell types in the TIME. In this review paper, we will discuss the challenges in the statistical analysis of mIF data and opportunities for further research.

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca 2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to examine the role of pancreatic islets in Cd-induced hyperglycemia. Male Sprague-Dawley rats were given daily subcutaneous doses of Cd at 0.6 mg/kg over 12 weeks. There was a resulting time-dependent increase in fasting blood glucose and altered insulin release in vitro. Islets isolated from control (saline-treated) and Cd-treated animals were incubated in low (0.5 mg/mL) or high (3 mg/mL) glucose conditions. Islets from 12 week Cd-treated animals had significantly less glucose-stimulated insulin release compared to islets from saline-treated control animals. The actual Cd content of isolated islets was 5 fold higher than the whole pancreas (endocrine + exocrine) and roughly 70% of that present in the renal cortex. Interestingly, islets isolated from Cd-treated animals and incubated in high glucose conditions contained significantly less Cd and zinc than those incubated in low glucose. These results show that within whole pancreatic tissue, Cd selectively accumulates in pancreatic islets and causes altered islet function that likely contributes to dysglycemia.

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M 1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M 1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M 1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site's function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis.

Osteoporosis is a bone disease that has no definite cure. Current treatments for osteoporosis are divided into two categories: anti-resorptive and anabolic. However, these treatments are not perfect and have considerable risks. In addition, bone quality often declines over time with these treatments. We designed a peptide, CK2.3, that has both anabolic and anti-resorptive effects on bone. We reported that CK2.3 induced osteoblastic mineralization, promoted bone formation, and suppressed osteoclastogenesis in vivo. The effect of CK2.3 to rescue an osteoporosis phenotype model has never been shown. In this study, we demonstrated the effect of CK2.3 in ovariectomized rats, a standard model of osteoporosis. We systemically injected CK2.3 at 2.3 µg/kg each day for five consecutive days. Micro-computed tomography indicated that CK2.3 increased bone mineral density, (bone volume/tissue volume) BV/TV and (trabecular number) TbN, and decreased (trabecular space) TbSp in the femoral head. Similarly, single photon absorptiometry showed that treatment with CK2.3 increased bone mineral density in the lumbar spine and the pelvis. Additionally, we observed increased femoral shaft stiffness with ovariectomized rats treated with CK2.3. We also detected no significant changes in the weight of organs such as the heart, lung, liver, kidney, and spleen. An advantage of CK2.3 over current treatments was that it not only promoted bone formation but also improved fracture resistance. In conclusion, we demonstrated CK2.3 as a new anabolic treatment for osteoporosis.

Background: Resiliency is the ability to prepare for, recover from, and adapt to stressors from adverse events. Social vulnerabilities (limited access to resources, political power, and representation; lack of social capital; aspects of the built environment; health inequities; and being in certain demographic categories) can impact resiliency. The Vietnamese population living along the Mississippi Gulf Coast is a community that has unique social vulnerabilities that impact their ability to be resilient to adverse events., Objectives: The purpose of this project was to address social vulnerability by implementing and evaluating a volunteer Community Health Advisor (CHA) project to enhance community resiliency in this community., Methods: A program implemented over 8 three-hour sessions was adapted from the Community Health Advisor Network curriculum that focused on healthy eating, preventing chronic conditions (hyperlipidemia, Diabetes, hypertension, cancer, poor mental health). Topics also included leadership and capacity development skills., Results: Participants (n=22) ranged from 35-84 years of age. Most were female (63.6%), married (45.5%), unemployed (63.6%), had annual incomes of <$10,000, and had high school diplomas (68.2%). Community concerns were crime (50.0%), volunteerism (40.0%), language barriers (35.0%), and food insecurity (30.0%). Approximately 75% had experienced war trauma and/or refugee camps, and 10% had experienced domestic violence. Scores on the Community Health Advisor Core Competency Assessment increased from pre-test to post-test (t=-5.962, df=11, p<0.0001), as did SF-8 scores (t=5.759, df=17, p<0.0001)., Conclusion: Strategies to reduce vulnerabilities in the Vietnamese community should include developing interventions that address health risks and strengths and focus on root causes of vulnerability., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Cholesteryl ester liquid crystals exhibit thermochromic properties related to the existence of a twisted nematic phase. We formulate ternary mixtures of cholesteryl benzoate (CB), cholesteryl pelargonate (CP), and cholesteryl oleyl carbonate (COC) to achieve thermochromic behavior. We aim to achieve thermochromic fibers by incorporating the liquid crystal formulations into electrospun fibers. Two methods of incorporating the liquid crystal (LC) are compared: (1) blend electrospinning and (2) coaxial electrospinning using the same solvent system for the liquid crystal. For blend electrospinning, intermolecular interactions seem to be important in facilitating fiber formation since addition of LC can suppress bead formation. Coaxial electrospinning produces fibers with higher nominal fiber production rates (g/hr) and with higher nominal LC content in the fiber (wt. LC/wt. polymer assuming all of the solvent evaporates) but larger fiber size distributions as quantified by the coefficient of variation in fiber diameter than blend electrospinning with a single nozzle. Importantly, our proof-of-concept experiments demonstrate that coaxially electrospinning with LC and solvent in the core preserves the thermochromic properties of the LC so that thermochromic fibers are achieved.

A limitation of using exosomes to their fullest potential is their limited secretion from cells, a major bottleneck to efficient exosome production and application. This is especially true for mesenchymal stem cells (MSCs), which can self-renew but have a limited expansion capacity, undergoing senescence after only a few passages, with exosomes derived from senescent stem cells showing impaired regenerative capacity compared to young cells. Here, we examined the effects of small molecule modulators capable of enhancing exosome secretion from MSCs. The treatment of MSCs with a combination of N-methyldopamine and norepinephrine robustly increased exosome production by three-fold without altering the ability of the MSC exosomes to induce angiogenesis, polarize macrophages to an anti-inflammatory phenotype, or downregulate collagen expression. These small molecule modulators provide a promising means to increase exosome production by MSCs., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: People have multi-faceted health care needs and consult a diverse range of health care practitioners (HCP) from both the conventional and complementary medicine healthcare sectors. The effective communication between HCP and with patients are obvious requisites to coordinating multidisciplinary care and shared decision making. Further, miscommunication is a leading cause of patient harm and is associated with reduced patient satisfaction, health literacy, treatment compliance and quality of life. In conventional healthcare settings, the differences in professional hierarchy, training, communication styles and culture are recognised communication barriers. Less is known about interprofessional communication (IPC) that includes traditional and complementary medicine (TCM) HCP. This review aims to summarise the experiences and perceptions of conventional and complementary HCP and identify factors that influence IPC. Methods: A qualitative rapid literature review was conducted. Six databases were searched to identify original research and systematic reviews published since 2009 and in English. Excluded were articles reporting original research outside of Australia that did not include TCM-HCP, already cited in a systematic review, or of low quality with a score of less than three on a critical appraisal skills programme (CASP) checklist. A thematic analysis of included studies was used to identify and explore important and recurring themes. Results: From the conducted searches, 18 articles were included, 11 of which reported data on complementary HCP and seven were literature reviews. Four key themes were identified that impact IPC: medical dominance, clarity of HCP roles, a shared vision, and education and training. Conclusion: IPC within and between conventional and complementary HCP is impacted by interrelated factors. A diverse range of initiatives that facilitate interprofessional learning and collaboration are required to facilitate IPC and help overcome medical dominance and interprofessional cultural divides.

Even though the Centers for Medicare and Medicaid Services is penalizing hospitals for readmissions, and postoperative prophylaxis has demonstrated reduced complications associated with deep vein thrombosis (DVT), few studies have examined patient compliance with (DVT) prophylaxis at home. A survey querying DVT prophylaxis management and adherence was administered to patients who were within the one to three-month postoperative period after a total knee or total hip replacement. A total of 103 patients completed the survey. A considerable number of patients (17.0%) were non-adherent to DVT prophylaxis. Patients had a lower understanding of the side effects of their DVT prophylaxis, with 30% responding that they had a poor to simple understanding. There is a high rate of non-compliance and there is a poor understanding of complications related to venous thromboembolism prophylaxis. As the population undergoing arthroplasties grows, this study demonstrates the importance of investigating the role of medication adherence in the rate of postoperative DVT., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm²/h) compared to passive delivery (12.83 ± 6.30 µg/cm²/h). For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm²/h was observed compared to 10.85 ± 0.11 µg/cm²/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only a 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm²/h versus 30.74 ± 1.32 µg/cm²/h). Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant., Competing Interests: The authors declare no conflict of interest.

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.