Search Results (18)

Machupo virus (MACV), a member of the Arenaviridae family and causative agent of Bolivian hemorrhagic fever, results in lethality rates of 25–35% in humans. Mice lacking the signal transducer and activator of transcription 1 (STAT-1^−/−) have previously been shown to succumb to MACV infection within 7–8 days via the intraperitoneal route. Despite these reports, we observed partial lethality in STAT-1^−/− mice following challenge with wild-type MACV. Serial sampling studies to evaluate the temporal progression of infection and pathologic changes after challenge revealed a two-phase disease course. The first phase was characterized by viral load and pathological lesions in the spleen, liver, and kidney followed by a second, lethal phase, defined by high viral titers and inflammation in the brain and spinal cord resulting in neurological manifestations and subsequent mortality. Tissue adaptation in the brains of challenged STAT-1^−/− mice resulted in a fully lethal model in STAT-1^−/− mice (mouse-adapted; maMACV). A similar two-phase disease course was observed following maMACV challenge, but more rapid dissemination of the virus to the brain and overall pathology in this region was observed. The outcome of these studies is a lethal small rodent model of MACV that recapitulates many aspects of human disease. Full article

Raymond Williams’s concept of the “structure of feeling” aims to describe the shared experiences, attitudes, and emotions of social groups at specific historical moments. However, this theory has been criticized for lacking a rigorous theoretical framework, clear definitions, and boundaries, as well as for failing to adequately explain its interaction with mainstream ideology. This paper attempts to address these issues through the lens of the Brazilian Liberation Theology movement. The “structure of feeling” established by Brazilian Liberation Theology departed from the traditional hierarchical system of the Church, aligning itself instead with emerging cultures and the practices of grassroots church communities. Under the repression of the military government, the mainstream Church began to accept certain aspects of Liberation Theology rather than viewing it solely as radical and threatening. Although Liberation Theology gradually waned after the fall of the military regime, its adjusted “structure of feeling”—devoid of its radical elements but still focused on social justice and poverty—profoundly impacted the global Catholic Church. The experience of the Brazilian Liberation Theology movement illustrates that a “structure of feeling” can transcend the dichotomy between consciousness and materiality and the crux lies in individuals discovering and asserting their own existence; such a “structure of feeling” can either emerge from within existing ideologies or challenge them directly; its relationship with mainstream ideology is significantly shaped by specific historical contexts; certain facets of emerging emotions are selectively incorporated into mainstream ideology, typically in ways that mitigate their more radical implications. Full article

Single-vesicle molecular profiling of cancer-associated extracellular vesicles (EVs) is increasingly being recognized as a powerful tool for cancer detection and monitoring. Mask and target dual imaging is a facile method to quantify the fraction of the molecularly targeted population of EVs in biofluids at the single-vesicle level. However, accurate and efficient dual imaging vesicle analysis has been challenging due to the interference of false signals on the mask images and the need to analyze a large number of images in clinical samples. In this work, we report a fully automatic dual imaging analysis method based on machine learning and use it with dual imaging single-vesicle technology (DISVT) to detect breast cancer at different stages. The convolutional neural network Resnet34 was used along with transfer learning to produce a suitable machine learning model that could accurately identify areas of interest in experimental data. A combination of experimental and synthetic data were used to train the model. Using DISVT and our machine learning-assisted image analysis platform, we determined the fractions of EpCAM-positive EVs and CD24-positive EVs over captured plasma EVs with CD81 marker in the blood plasma of pilot HER2-positive breast cancer patients and compared to those from healthy donors. The amount of both EpCAM-positive and CD24-positive EVs was found negligible for both healthy donors and Stage I patients. The amount of EpCAM-positive EVs (also CD81-positive) increased from 18% to 29% as the cancer progressed from Stage II to III. No significant increase was found with further progression to Stage IV. A similar trend was found for the CD24-positive EVs. Statistical analysis showed that both EpCAM and CD24 markers can detect HER2-positive breast cancer at Stages II, III, or IV. They can also differentiate individual cancer stages except those between Stage III and Stage IV. Due to the simplicity, high sensitivity, and high efficiency, the DISVT with the AI-assisted dual imaging analysis can be widely used for both basic research and clinical applications to quantitatively characterize molecularly targeted EV subtypes in biofluids. Full article

Traumatic heterotopic ossification (HO) is frequently observed in Service Members following combat-related trauma. Estimates suggest that ~65% of wounded warriors who suffer limb loss or major extremity trauma will experience some type of HO formation. The development of HO delays rehabilitation and can prevent the use of a prosthetic. To date there are limited data to suggest a standard mechanism for preventing HO. This may be due to inadequate animal models not producing a similar bone structure as human HO. We recently showed that traumatic HO growth is possible in an ovine model. Within that study, we demonstrated that 65% of sheep developed a human-relevant hybrid traumatic HO bone structure after being exposed to a combination of seven combat-relevant factors. Although HO formed, we did not determine which traumatic factor contributed most. Therefore, in this study, we performed individual and various combinations of surgical/traumatic factors to determine their individual contribution to HO growth. Outcomes showed that the presence of mature biofilm stimulated a large region of bone growth, while bone trauma resulted in a localized bone response as indicated by jagged bone at the linea aspera. However, it was not until the combinatory factors were included that an HO structure similar to that of humans formed more readily in 60% of the sheep. In conclusion, data suggested that traumatic HO growth can develop following various traumatic factors, but a combination of known instigators yields higher frequency size and consistency of ectopic bone. Full article

We previously reported that an aryl hydrocarbon receptor (AhR) ligand, indole-3-carbinol (I3C), was effective at reducing colitis severity through immune cell-mediated interleukin-22 (IL-22) production. Intestinal epithelial cells (IECs) are also involved in regulating colitis, so we investigated their AhR-mediated mechanisms in the current report. A transcriptome analysis of IECs in wildtype (WT) mice revealed that during colitis, I3C regulated select mucin proteins, which could be attributed to goblet cell development. To address this, experiments under in vivo colitis (mice) or in vitro colon organoid conditions were undertaken to determine how select mucin proteins were altered in the absence or presence of AhR in IECs during I3C treatment. Comparing WT to IEC-specific AhR knockout mice (AhR^ΔIEC), the results showed that AhR expression was essential in IECs for I3C-mediated protection during colitis. AhR-deficiency also impaired mucin protein expression, particularly mucin 2 (Muc2), independently of IL-22. Collectively, this report highlights the important role of AhR in direct regulation of Muc2. These results provide justification for future studies aimed at determining how AhR might regulate select mucins through mechanisms such as direct transcription binding to enhance production. Full article

Adobe has been used globally for millennia. In the US Southwest, cultural heritage sites made of adobe materials have lasted hundreds of years in an arid/semi-arid environment. A common prediction across multiple climate change models, however, is that rainfall intensity will increase in the US Southwest. This increased erosivity threatens the long-term protection and preservation of these sites, and thus resource managers are faced with selecting effective conservation practices. For this reason, modeling tools are needed to predict climate change impacts and plan for adaptation strategies. Many existing strategies, including patching damaged areas, building protective caps and shelter coating walls are already commonly utilized. In this study, we modeled adobe block construction, subjected extant walls to a local 100-year return interval rainfall intensity, and tested earthen-coat-based strategies to minimize the deterioration of earthen fabric. Findings from the resultant linear models indicate that the patching of earthen architecture alone will not prevent substantial damage, while un-amended encapsulation coats and caps provide similar, and significantly greater protection than patching. The use of this model will enable local heritage resource managers to better target preservation methods for a return on investment of the material and labor costs, resulting in better preservation overall and the retention of culturally valuable resources. Full article

Acknowledging an undeniable need for innovation, this paper offers a qualitative assessment for recognition and policy advocacy for superior innovations—for new wood products and processes offering more benefits and fewer drawbacks than other innovations. The paper highlights the irrationality of using the limited natural and human-made goods of the world to produce and consume inferior innovations, especially when they fail to mitigate or, in fact, contribute to worsening climate change. Raymond Williams’ “structures of feeling” are used to disclose evaluative commitments associated with the “new” characteristic of industrialized and indigenous civilizations toward illuminating potential pathways for halting an otherwise seemingly unstoppable engine of climate change from pushing all of life on Earth over its precipice. Discussing how the “new” is always implicated in the “old,” decision-making and design methods applicable over the whole of the value chain are proposed for generating “new” innovations and processes that are genuinely able to change the current world trajectory of our species. Future research is also discussed. Full article

Perspectives of cancer survivors, caregivers, and social workers as key stakeholders on the clinical management of financial toxicity (FT) are critical to identify opportunities for better FT management. Semi-structured interviews (cancer survivors, caregivers) and a focus group (social workers) were undertaken using purposive sampling at a quaternary public hospital in Australia. People with any cancer diagnosis attending the hospital were eligible. Data were analysed using inductive-deductive content analysis techniques. Twenty-two stakeholders (n = 10 cancer survivors of mixed-cancer types, n = 5 caregivers, and n = 7 social workers) participated. Key findings included: (i) genuine concern for FT of cancer survivors and caregivers shown through practical support by health care and social workers; (ii) need for clarity of role and services; (iii) importance of timely information flow; and (iv) proactive navigation as a priority. While cancer survivors and caregivers received financial assistance and support from the hospital, the lack of synchronised, shared understanding of roles and services in relation to finance between cancer survivors, caregivers, and health professionals undermined the effectiveness and consistency of these services. A proactive approach to anticipate cancer survivors’ and caregivers’ needs is recommended. Future research may develop and evaluate initiatives to manage cancer survivors and families FT experiences and outcomes. Full article

Cancer-associated malnutrition, or cachexia, stemming from cancer or its treatments, is particularly prevalent in metastatic cancers, and is often interrelated with sarcopenia and frailty. Evidence suggests that dietary supplements play a role in managing these conditions. As metastatic cancer cells are associated with notable genomic and phenotypic alterations, response to dietary supplements may differ between metastatic and non-metastatic cancers. However, research in this area is lacking. This scoping review aims to identify the dietary supplements that have been studied in patients with metastatic cancers and malnutrition-related conditions, along with their proposed effects, mechanisms, outcome measures, and tools used. A systematic search was conducted across databases, including MEDLINE, EMBASE, CINAHL, and clinical trial registries. Of the initial 6535 records screened, a total of 48 studies were included, covering a range of dietary supplements—vitamins, minerals, antioxidants, proteins, amino acids, fatty acids, fiber, and others. While the types of dietary supplements included varied across cancer types, omega-3 and carnitine were investigated most often. Proposed relevant attributes of dietary supplements included their antioxidant, anti-inflammatory, anti-cancer, and immunomodulatory properties. Overall, there was a paucity of interventional studies, and more randomized controlled trials are warranted. Full article

Laboratory cultures of two ‘biosynthetically talented’ bacterial strains harvested from tropical and temperate Pacific Ocean sediment habitats were examined for the production of new natural products. Cultures of the tropical Salinispora arenicola strain RJA3005, harvested from a PNG marine sediment, produced salinorcinol (3) and salinacetamide (4), which had previously been reported as products of engineered and mutated strains of Amycolatopsis mediterranei, but had not been found before as natural products. An S. arenicola strain RJA4486, harvested from marine sediment collected in the temperate ocean waters off British Columbia, produced the new aminoquinone polyketide salinisporamine (5). Natural products 3, 4, and 5 are putative shunt products of the widely distributed rifamycin biosynthetic pathway. Full article

The purpose of this study was to examine the effects of a single acute dose of yohimbine hydrochloride on repeated anaerobic sprint ability. Physically active females (n = 18) completed two separate repeated supramaximal sprint trials each with a different single-dose treatment: placebo (PL; gluten-free corn starch) or yohimbine hydrochloride (YHM; 2.5 mg). For each trial, participants consumed their respective treatment 20 min before exercise. Following a warm-up, participants completed 3 × 15 s Wingate anaerobic tests (WAnTs) separated by 2 min of active recovery. A capillary blood sample was obtained pre- and immediately post-exercise to measure blood concentrations of lactate (LA), epinephrine (EPI), and norepinephrine (NE). Heart rate (HR) and rate of perceived exertion (RPE) were measured following each WAnT. Findings showed that mean power (p < 0.001; η² = 0.024), total work (p < 0.001; η² = 0.061), and HR (p < 0.001; η² = 0.046), were significantly higher with YHM supplementation versus PL. Fatigue index (p < 0.001; η² = 0.054) and post-exercise LA (p < 0.001; d = 1.26) were significantly lower with YHM compared to PL. YHM resulted in significantly higher EPI concentrations versus PL (p < 0.001; η² = 0.225) pre- and post-exercise while NE only increased as a function of time (p < 0.001; η² = 0.227) and was unaffected by treatment. While RPE increased after each WAnT, no differences between treatments were observed (p = 0.539; η² < 0.001). Together, these results suggest that acute YHM ingestion imparts ergogenic benefits which may be mediated by lower blood LA and fatigue concomitantly occurring with blood EPI increases. Thus, YHM may improve sprint performance although more mechanistic study is warranted to accentuate underlying processes mediating performance enhancement. Full article

Implicit racial bias is a persistent and pervasive challenge within healthcare education and training settings. A recent systematic review reported that 84% of included studies (31 out of 37) showed evidence of slight to strong pro-white or light skin tone bias amongst healthcare students and professionals. However, there remains a need to improve understanding about its impact on healthcare students and how they can be better supported. This narrative review provides an overview of current evidence regarding the role of implicit racial bias within healthcare education, considering trends, factors that contribute to bias, and possible interventions. Current evidence suggests that biases held by students remain consistent and may increase during healthcare education. Sources that contribute to the formation and maintenance of implicit racial bias include peers, educators, the curriculum, and placements within healthcare settings. Experiences of implicit racial bias can lead to psychosomatic symptoms, high attrition rates, and reduced diversity within the healthcare workforce. Interventions to address implicit racial bias include an organizational commitment to reducing bias in hiring, retention, and promotion processes, and by addressing misrepresentation of race in the curriculum. We conclude that future research should identify, discuss, and critically reflect on how implicit racial biases are enacted and sustained through the hidden curriculum and can have detrimental consequences for racial and ethnic minority healthcare students. Full article

Discrimination is a fundamental determinant of health and health inequities. However, despite the high prevalence of discrimination exposure, there is limited evidence specific to Indigenous populations on the link between discrimination and health. This study employs a validated measure to quantify experiences of everyday discrimination in a national sample of Aboriginal and Torres Strait Islander (Australia’s Indigenous peoples) adults surveyed from 2018 to 2020 (≥16 years, n = 8108). It quantifies Prevalence Ratios (PRs) and 95% Confidence Intervals (CIs) for wellbeing outcomes by level of discrimination exposure, and tests if associations vary by attribution of discrimination to Indigeneity. Of the participants, 41.5% reported no discrimination, 47.5% low, and 11.0% moderate-high. Discrimination was more commonly reported by younger versus older participants, females versus males, and those living in remote versus urban or regional areas. Discrimination was significantly associated in a dose-response manner, with measures of social and emotional wellbeing, culture and identity, health behaviour, and health outcomes. The strength of the association varied across outcomes, from a 10–20% increased prevalence for some outcomes (e.g., disconnection from culture (PR = 1.08; 95% CI: 1.03, 1.14), and high blood pressure (1.20; 1.09, 1.32)), to a five-fold prevalence of alcohol dependence (4.96; 3.64, 6.76), for those with moderate-high versus no discrimination exposure. The association was of consistent strength and direction whether attributed to Indigeneity or not—with three exceptions. Discrimination is associated with a broad range of poor wellbeing outcomes in this large-scale, national, diverse cohort of Aboriginal and Torres Strait Islander adults. These findings support the vast potential to improve Aboriginal and Torres Strait Islander peoples’ wellbeing, and to reduce Indigenous-non-Indigenous inequities, by reducing exposure to discrimination. Full article

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development. Full article

Despite the existence of safe and efficacious human and animal rabies vaccines, millions of people remain at risk of exposure to this deadly zoonotic disease through bites of infected dogs. Sub-Saharan African countries, such as the Democratic Republic of the Congo (DRC), bear the highest per capita death rates from rabies where dog vaccination and availability of lifesaving post-exposure prophylaxis (PEP) is scarce. Mass dog vaccination is the most cost-effective and sustainable approach to prevent human rabies deaths. We conducted a cross-sectional household survey in a rabies-affected community in Matadi, DRC, to estimate the size of the owned dog population and dog bite incidence and assess knowledge and practices regarding rabies, as preparation for future mass dog vaccination campaigns. Our study revealed that the owned dog population in Matadi was almost ten times larger than assumed by local veterinary officials, with a large proportion of free-roaming unvaccinated dogs. The annual dog bite incidence of 5.2 per 1000 person years was high, whereas community rabies knowledge was low resulting in poor practices. Given these findings, human rabies deaths are likely to occur in this community. Lack of disease awareness could negatively affect participation in future mass dog vaccination campaigns. A public sensitization campaign is needed to promote appropriate rabies prevention (washing bite wounds and PEP) and control (dog vaccination) measures in this community. Full article