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Post-traumatic osteoarthritis (PTOA) is a painful joint disease characterized by the degradation of bone, cartilage, and other connective tissues in the joint. PTOA is initiated by trauma to joint-stabilizing tissues, such as the anterior cruciate ligament, medial meniscus, or by intra-articular fractures. In humans, ~50% of joint injuries progress to PTOA, while the rest spontaneously resolve. To better understand molecular programs contributing to PTOA development or resolution, we examined injury-induced fluctuations in immune cell populations and transcriptional shifts by single-cell RNA sequencing of synovial joints in PTOA-susceptible C57BL/6J (B6) and PTOA-resistant MRL/MpJ (MRL) mice. We identified significant differences in monocyte and macrophage subpopulations between MRL and B6 joints. A potent myeloid-driven anti-inflammatory response was observed in MRL injured joints that significantly contrasted the pro-inflammatory signaling seen in B6 joints. Multiple CD206+ macrophage populations classically described as M2 were found enriched in MRL injured joints. These CD206+ macrophages also robustly expressed Trem2, a receptor involved in inflammation and myeloid cell activation. These data suggest that the PTOA resistant MRL mouse strain displays an enhanced capacity of clearing debris and apoptotic cells induced by inflammation after injury due to an increase in activated M2 macrophages within the synovial tissue and joint space.

Dementia prevention in Africa is critically underexplored, despite the continents high prevalence of modifiable risk factors. With a predominantly young and middle-aged population, Africa presents a prime opportunity to implement evidence-based strategies that could significantly reduce future dementia cases and mitigate its economic impact. The multinational Africa-FINGERS program offers an innovative solution, pioneering culturally sensitive, multidomain interventions tailored to the unique challenges of the region.  Leveraging insights from landmark global studies such as Worldwide-FINGERS and Alzheimers Disease Neuroimaging Initiative, the program employs a multideterminant precision prevention framework, grounded in community based systems dynamics. Africa-FINGERS further integrates cutting-edge state-of-the-art multimodal biomarker evaluations tailored to regional contexts, with the goal of advancing brain health and establishing a global standard for dementia prevention. This groundbreaking initiative highlights the potential for scalableand sustainable interventions, thus is poised to transform dementia risk reduction efforts across the continent. HIGHLIGHTS: Dementia rates are escalating in Africa, largely due to longer life spans and increased prevalence of modifiable risk factors. Yet, few regional interventions have directly targeted lifestyle factors to reduce dementia risk. The multinational Africa-FINGERS study will address this gap by adapting the successful FINGERS lifestyle intervention to African populations. Africa-FINGERS will pioneer a culturally informed, multidomain dementia risk reduction intervention in the African region through feasibility dementia prevention trials in rural and urban sites across Kenya and Nigeria in the first instance, enrolling 600 at-risk adults (≥ 50 years). The program adopts participatory research methods to develop culturally appropriate interventions and build infrastructure to evaluate dementia biomarkers from ante and post mortem samples. A cost-effectiveness analysis will be conducted to guide the strategic implementation of Africa-FINGERS into regional health systems. The Africa-FINGERS strategy aligns with the Worldwide-FINGERS framework and integrates the global Alzheimers Disease Neuroimaging Initiative approach, emphasizing multimodal analysis.

Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

UNLABELLED: Coccidioidomycosis, also known as Valley fever, is a disease caused by the fungal pathogen Coccidioides. Unfortunately, patients are often misdiagnosed with bacterial pneumonia, leading to inappropriate antibiotic treatment. The soil Bacillus subtilis-like species exhibits antagonistic properties against Coccidioides in vitro; however, the antagonistic capabilities of host microbiota against Coccidioides are unexplored. We sought to examine the potential of the tracheal and intestinal microbiomes to inhibit the growth of Coccidioides in vitro. We hypothesized that an uninterrupted lawn of microbiota obtained from antibiotic-free mice would inhibit the growth of Coccidioides, while partial in vitro depletion through antibiotic disk diffusion assays would allow a niche for fungal growth. We observed that the microbiota grown on 2×GYE (GYE) and Columbia colistin and nalidixic acid with 5% sheeps blood agar inhibited the growth of Coccidioides, but microbiota grown on chocolate agar did not. Partial depletion of the microbiota through antibiotic disk diffusion revealed diminished inhibition and comparable growth of Coccidioides to controls. To characterize the bacteria grown and identify potential candidates contributing to the inhibition of Coccidioides, 16S rRNA sequencing was performed on tracheal and intestinal agar cultures and murine lung extracts. We found that the host bacteria likely responsible for this inhibition primarily included Lactobacillus and Staphylococcus. The results of this study demonstrate the potential of the host microbiota to inhibit the growth of Coccidioides in vitro and suggest that an altered microbiome through antibiotic treatment could negatively impact effective fungal clearance and allow a niche for fungal growth in vivo. IMPORTANCE: Coccidioidomycosis is caused by a fungal pathogen that invades the host lungs, causing respiratory distress. In 2019, 20,003 cases of Valley fever were reported to the CDC. However, this number likely vastly underrepresents the true number of Valley fever cases, as many go undetected due to poor testing strategies and a lack of diagnostic models. Valley fever is also often misdiagnosed as bacterial pneumonia, resulting in 60%-80% of patients being treated with antibiotics prior to an accurate diagnosis. Misdiagnosis contributes to a growing problem of antibiotic resistance and antibiotic-induced microbiome dysbiosis; the implications for disease outcomes are currently unknown. About 5%-10% of symptomatic Valley fever patients develop chronic pulmonary disease. Valley fever causes a significant financial burden and a reduced quality of life. Little is known regarding what factors contribute to the development of chronic infections and treatments for the disease are limited.

Abstract People with severe mental illness have high rates of obesity, type 2 diabetes, and cardiovascular disease. Emerging evidence suggests that metabolic dysfunction may be causally linked to the risk of severe mental illness. However, more research is needed to identify reliable metabolic markers which may have an impact on mental health outcomes, and to determine the mechanisms behind their impact. In the METPSY research study, we will investigate the relationship between metabolic markers and clinical outcomes of severe mental illness in young adults. We will recruit 120 young adults aged 16–25 years living in Scotland with major depressive disorder, bipolar disorder, schizophrenia, or no severe mental illness (controls) for a prospective observational study. We will assess clinical symptoms at three in-person visits (baseline, 6 months, and 12 months) using the Structured Clinical Interview for DSM-5, and collect blood samples at each of these visits for agnostic profiling of metabolic biomarkers through an untargeted metabolomic screen, using the rapid hydrophilic interaction liquid chromatography ion mobility mass spectrometry method (RHIMMS). Participants will also complete remote assessments at 3 and 9 months after the baseline visit: Ecological Momentary Assessments to measure mental health, wrist actigraphy to measure rhythms of rest and activity, and continuous glucose monitoring to measure metabolic changes. Throughout the 12-month enrolment period, we will also measure objective markers of sleep using a radar sleep monitor (Somnofy). Using advanced statistical techniques and machine learning analysis, we will seek to better understand the mechanisms linking metabolic health with mental health in young adults with schizophrenia, bipolar disorder, and severe depression. Clinical trial number: Not applicable

Institutional transformation and inclusion have slowly become more prominent in the strategies of historically white institutions in South Africa. Despite these efforts, progress towards these goals has been limited. In this article, we reflect on our conversations about transforming our curricula and teaching practices as an interdisciplinary Community of Practice. Our conversations grappled with the lack of curricular transformation at Stellenbosch University, despite its aspirational transformation plan. We argue that difficult interdisciplinary conversations are key to interrupting our teaching practices and are crucial in the decolonising process. These conversations must be ongoing and enduring, because through sharing our stories we support agents of curriculum transformation in our different contexts. Our conceptual conversations explored various theories about decoloniality, and here we employ ubuntu pedagogy, as well as the concepts of redistribution, recognition and representation from social justice theory. We harness the collaborative energy of an interdisciplinary Community of Practice, with its associated storytelling, reading, writing and reflecting to harness the diversity of personal and disciplinary perspectives. We include some reflective vignettes to illustrate our process. Contribution: The relevance of this study, beyond our contexts, arises from a gap in the decolonising process, from its theory to its practice. We argue that even a good institutional transformation plan will not guarantee the decoloniality of curricula. More is needed. Systemic change is needed, and difficult interdisciplinary conversations are part of this process. There must be recognition and representation of marginalised voices and specific context-related redistribution of curricula, so that transformation plans and theories can take effect.

Technology is key to making education systems more resilient to disruptions. In the South African higher education sector, technology will continue to play a much larger role than the years preceding the COVID-19 pandemic. Technology, however, cannot replace the value gained through social contact and concerns about relational disengagement in curricular, co-curricular and extra-curricular spaces have been noted. Drawing on large-scale qualitative data collected as part of the South African Survey of Student Engagement, this article explores what students consider as the most important factors in supporting their learning and development and how these factors might be translated to technologically enhanced learning and teaching spaces. Such insights from students' experiences could inform blended learning and teaching spaces that leverage technology to enhance relational engagement.

The development of new antibiotics has stalled, and novel strategies are needed as we enter the age of antibiotic resistance. Certain naturally occurring clays have been shown to be effective in killing antibiotic resistant bacteria. However, these natural clays are too variable to be used in clinical settings. Our study shows that synthetic antibacterial minerals exhibit potent antibacterial activity against topical MRSA infections and increase the rate of wound closure relative to controls. The antibacterial minerals maintain a redox cycle between Fe2+/Fe3+ and the surfaces of pyrite minerals, which act as a semiconductor and produce reactive oxygen species (ROS), while smectite minerals act as a cation exchange reservoir. Acidic conditions are maintained throughout the application of the hydrated minerals and can mitigate the alkaline pH conditions observed in chronic non-healing wounds. These results provide evidence for the strategy of iron overload to combat antibiotic resistant infections through the maintained release of Fe2+ and generation of ROS via distinct geochemical reactions that can break the chronic wound damage cycle.

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long-Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Valley fever or coccidioidomycosis is a pulmonary infection caused by species of Coccidioides fungi that are endemic to California and Arizona. Skeletal coccidioidomycosis accounts for about half of disseminated infections, with the vertebral spine being the preferred site of dissemination. Most cases of skeletal coccidioidomycosis progress to bone destruction or spread to adjacent structures such as joints, tendons, and other soft tissues, causing significant pain and restricting mobility. Manifestations of such cases are usually nonspecific, making diagnosis very challenging, especially in non-endemic areas. The lack of basic knowledge and research data on the mechanisms defining susceptibility to extrapulmonary infection, especially when it involves bones and joints, prompted us to survey available clinical and animal data to establish specific research questions that remain to be investigated. In this review, we explore published literature reviews, case reports, and case series on the dissemination of coccidioidomycosis to bones and/or joints. We highlight key differential features with other conditions and opportunities for mechanistic and basic research studies that can help develop novel diagnostic, prognostic, and treatment strategies.

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O2) and standard (21% O2) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, this work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening.

We have investigated phenological shifts in autumn- and winter-spawning Atlantic herring (Clupea harengus) in the Eastern English Channel and the Southern North Sea (Downs component), in relation to temperature and the availability of potential zooplanktonic prey (Calanus finmarchicus, Calanus helgolandicus, Temora longicornis). A two-tiered approach building on the monthly distribution of commercial herring landings was developed, which consisted of, (1) calculating the timing and duration of spawning season based on estimated deviations from basic harmonic signals and, (2) analysing their inter-annual variations in relation to biotic (zooplankton abundance) and abiotic (temperature) environmental variables through time series analyses. The start, midpoint and ending of herring spawning season were increasingly delayed over the period 1999-2021, a process which was correlated with the abundance of Calanus finmarchicus. The resulting duration of spawning season slightly decreased. Direct effects of sea temperatures on any phenological metrics could not be clearly evidenced. Different ecological processes were likely involved in the start and ending of spawning season. Additional covariates (including size/age composition, the biotic and abiotic factors other than those examined in our study) could contribute to a better explanation of the phenological drift in Downs herring spawning.

Post-traumatic osteoarthritis (PTOA) is a painful joint disease characterized by the degradation of bone, cartilage, and other connective tissues in the joint. PTOA is initiated by trauma to joint-stabilizing tissues, such as the anterior cruciate ligament, medial meniscus, or by intra-articular fractures. In humans, ~50% of joint injuries progress to PTOA, while the rest spontaneously resolve. To better understand molecular programs contributing to PTOA development or resolution, we examined injury-induced fluctuations in immune cell populations and transcriptional shifts by single-cell RNA sequencing of synovial joints in PTOA-susceptible C57BL/6J (B6) and PTOA-resistant MRL/MpJ (MRL) mice. We identified significant differences in monocyte and macrophage subpopulations between MRL and B6 joints. A potent myeloid-driven anti-inflammatory response was observed in MRL injured joints that significantly contrasted the pro-inflammatory signaling seen in B6 joints. Multiple CD206+ macrophage populations classically described as M2 were found enriched in MRL injured joints. These CD206+ macrophages also robustly expressed Trem2, a receptor involved in inflammation and myeloid cell activation. These data suggest that the PTOA resistant MRL mouse strain displays an enhanced capacity of clearing debris and apoptotic cells induced by inflammation after injury due to an increase in activated M2 macrophages within the synovial tissue and joint space.

The increasing prevalence of remote working and the challenges it presents underscores the need for alternative technologies that can provide a more healthy, natural and social remote meeting experience. However, there is a limited understanding of how such technologies compare to other modalities, especially face-to-face communication. This study investigates the impact of three meeting modalities - face-to-face, videoconferencing, and virtual reality (VR) - on participants’ experience of social presence, wellbeing, and task engagement during a meeting involving a negotiation task. Despite the hypothesis that these experiences would significantly differ across modalities, no such differences were found. We suspect that characteristics of the meeting participants and the negotiation task, the meeting duration, as well as the measurements used have moderated the effect of meeting modality on experience. The VR modality was however perceived as more enjoyable, suggesting that immersive technologies like VR hold potential for enhancing the remote meeting experience. The results also underscore that there is no one-size fits all solution when it comes to choosing the best meeting modality. The study stresses the need for ongoing research to optimize the remote meeting experience in the context of different meeting objectives and practical considerations.

Summary: The use of archival formalin-fixed paraffin-embedded (FFPE) tissue samples for biochemical analyses is problematic because of the formation of a Schiff base, leading to low protein and metabolite yields during analytical extractions. Here, we overcome this issue using a unified protocol on FFPE tissue for metabolomics and proteomics analyses. Using 20 mg of wet mass tissue, this protocol consistently extracted more than 50 metabolites (across 11 classes of metabolites) and over 900 proteins. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

A substantial body of evidence links green space to positive health outcomes. Beyond the availability of dedicated green spaces such as parks and the overall presence of vegetation and trees, visual exposure to greenery has also been shown to be important for well-being. Enhancing visual access to greenery may thus represent a pathway to promoting health and well-being. However, at regional or national scales, insights into disparities in visual access to greenery remain scarce. Most research and policy efforts rely on two-dimensional (top-down) data, which often fails to accurately capture the amount of greenery visible from individual perspectives, such as from within homes.This study builds on the work of Labib et al. [20], who developed a high-resolution (5 m grid) Viewshed Greenness Visibility Index (VGVI) for the Greater Manchester area (UK). By introducing technical improvements that significantly increased computational efficiency, we extended this approach to create a comprehensive VGVI map for Flanders, the northern region of Belgium. The resulting map enabled a broad assessment of VGVI disparities across Flanders. Our findings reveal evidence of distributive environmental injustice, as demonstrated by a strong negative correlation (Spearman's Rho = -0.48) between neighbourhood deprivation levels and VGVI scores. In Flanders, residents of more deprived neighbourhoods are exposed to significantly lower levels of visible greenery.We further explored the differences and similarities between traditional top-down greenness mapping and VGVI, which provides an eye-level perspective. Although a strong positive correlation was observed at the regional scale (Pearson's r = 0.80), this relationship weakens at the local level. Our findings suggest that VGVI analysis is particularly valuable at smaller geographic scales, making it especially relevant for research or spatial policies that address disparities in individual living conditions or target specific locations, such as schools, nurseries, hospitals, retirement homes, and community centres.

Post traumatic osteoarthritis (PTOA) is a form of secondary osteoarthritis (OA) that develops in ~50% of cases of severe articular joint injuries and leads to chronic and progressive degradation of articular cartilage and other joint tissues. PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6 weeks before anterior cruciate ligament (ACL) rupture in STR/ort mice combined with lipopolysaccharide (LPS)-induced systemic inflammation. STR/ort mice develop spontaneous OA as well as a more severe PTOA phenotype than C57Bl/6J mice. By 6 weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic-treated (AB) STR/ort mice than in the untreated STR/ort controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in STR/ort mice. The AB- or AB+LPS-treated STR/ort injured joints more closely resembled the C57Bl/6J VEH OA phenotypes than the vehicle- or LPS-treated STR/ort, suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Patients with bone metastases may experience debilitating pain, neurological conditions, increased risk of pathological fractures, and death. A deeper understanding of the bone microenvironment, the molecular biology of cancer types prone to metastasis, and how bone physiology promotes cancer growth, may help to uncover targeted treatment options. The purpose of this paper is to outline the current concepts relevant to topics including bone remodeling, angiogenesis, and immunomodulation as it relates to metastatic bone disease.

Molecular oxygen levels vary during development and disease. Adaptations to decreased oxygen bioavailability (hypoxia) are mediated by hypoxia-inducible factor (HIF) transcription factors. HIFs are composed of an oxygen-dependent α subunit (HIF-α), of which there are two transcriptionally active isoforms (HIF-1α and HIF-2α), and a constitutively expressed β subunit (HIFβ). Under normoxic conditions, HIF-α is hydroxylated via prolyl hydroxylase domain (PHD) proteins and targeted for degradation via Von Hippel-Lindau (VHL). Under hypoxic conditions, hydroxylation via PHD is inhibited, allowing for HIF-α stabilization and induction of target transcriptional changes. Our previous studies showed that Vhl deletion in osteocytes (Dmp1-cre; Vhl f/f ) resulted in HIF-α stabilization and generation of a high bone mass (HBM) phenotype. The skeletal impact of HIF-1α accumulation has been well characterized; however, the unique skeletal impacts of HIF-2α remain understudied. Because osteocytes orchestrate skeletal development and homeostasis, we investigated the role of osteocytic HIF-α isoforms in driving HBM phenotypes via osteocyte-specific loss-of-function and gain-of-function HIF-1α and HIF-2α mutations in C57BL/6 female mice. Deletion of Hif1a or Hif2a in osteocytes showed no effect on skeletal microarchitecture. Constitutively stable, degradation-resistant HIF-2α (HIF-2α cDR), but not HIF-1α cDR, generated dramatic increases in bone mass, enhanced osteoclast activity, and expansion of metaphyseal marrow stromal tissue at the expense of hematopoietic tissue. Our studies reveal a novel influence of osteocytic HIF-2α in driving HBM phenotypes that can potentially be harnessed pharmacologically to improve bone mass and reduce fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

In the aftermath of the COVID-19 pandemic, the prevalence of remote business meetings through videoconferencing platforms such as Zoom and Microsoft Teams has substantially increased. While remote meetings provide benefits such as increased efficiency, flexibility, and environmental sustainability, they may also reduce meeting engagement, hamper conversational flow, or cause fatigue. This study investigates whether social Extended Reality technology can serve as a viable alternative for videoconferencing for remote business meetings. Employees from three distinct organizations in the Netherlands convened through Meta Horizon Workrooms, a collaborative virtual platform. Afterwards, participants were inquired about their perspectives on Extended Reality during semi-structured interviews that focused on the meeting’s engagement, conversational flow and the system’s usability. The study’s findings highlight the benefits of Extended Reality for remote business meetings, as participants reported improved interaction, more togetherness, and a better conversational flow. Embodied virtual reality was identified as useful in supporting nonverbal communication by allowing for more natural interaction and turn-taking, similar to face-to-face interactions. Nonetheless, challenges associated with avatar realism and the developing technological state of Extended Reality present barriers, rendering current widespread adoption a difficult task.

Mechanical unloading causes rapid loss of bone structure and strength, which gradually recovers after resuming normal loading. However, it is not well established how this adaptation to unloading and reloading changes with age. Clinically, elderly patients are more prone to musculoskeletal injury and longer periods of bedrest, therefore it is important to understand how periods of disuse will affect overall skeletal health of aged subjects. Bone also undergoes an age-related decrease in osteocyte density, which may impair mechanoresponsiveness. In this study, we examined bone adaptation during unloading and subsequent reloading in mice. Specifically, we examined the differences in bone adaptation between young mice (3-month-old), old mice (18-month-old), and transgenic mice that exhibit diminished osteocyte density at a young age (3-month-old BCL-2 transgenic mice). Mice underwent 14 days of hindlimb unloading followed by up to 14 days of reloading. We analyzed trabecular and cortical bone structure in the femur, mechanical properties of the femoral cortical diaphysis, osteocyte density and cell death in cortical bone, and serum levels of inflammatory cytokines. We found that young mice lost ~10% cortical bone volume and 27-42% trabecular bone volume during unloading and early reloading, with modest recovery of metaphyseal trabecular bone and near total recovery of epiphyseal trabecular bone, but no recovery of cortical bone after 14 days of reloading. Old mice lost 12-14% cortical bone volume and 35-50% trabecular bone volume during unloading and early reloading but had diminished recovery of trabecular bone during reloading and no recovery of cortical bone. In BCL-2 transgenic mice, no cortical bone loss was observed during unloading or reloading, but 28-31% trabecular bone loss occurred during unloading and early reloading, with little to no recovery during reloading. No significant differences in circulating inflammatory cytokine levels were observed due to unloading and reloading in any of the experimental groups. These results illustrate important differences in bone adaptation in older and osteocyte deficient mice, suggesting a possible period of vulnerability in skeletal health in older subjects during and following a period of disuse that may affect skeletal health in elderly patients.

Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest forms of cancer with very few treatment options. The 5-year survival rate for PDAC is 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, and Cdh11 inhibition significantly extended survival in mice with PDAC. However, the mechanisms by which Cdh11 deficiency influences PDAC progression and anti-tumor immune responses have yet to be fully elucidated. To investigate Cdh11-deficiency induced changes in PDAC tumor microenvironment (TME), we crossed p48-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice with Cdh11+/- mice and performed single-cell RNA sequencing (scRNA-seq) of the non-immune (CD45-) and immune (CD45+) compartment of KPC tumor-bearing Cdh11 proficient (KPC-Cdh11+/+) and Cdh11 deficient (KPC-Cdh11+/-) mice. Our analysis showed that Cdh11 is expressed primarily in cancer-associated fibroblasts (CAFs) and at low levels in epithelial cells undergoing epithelial-to-mesenchymal transition (EMT). Cdh11 deficiency altered the molecular profile of CAFs, leading to a decrease in the expression of myofibroblast markers such as Acta2 and Tagln and cytokines such as Il6, Il33 and Midkine (Mdk). We also observed a significant decrease in the presence of monocytes/macrophages and neutrophils in KPC-Cdh11+/- tumors while the proportion of T cells was increased. Additionally, myeloid lineage cells from Cdh11-deficient tumors had reduced expression of immunosuppressive cytokines that have previously been shown to play a role in immune suppression. In summary, our data suggests that Cdh11 deficiency significantly alters the fibroblast and immune microenvironments and contributes to the reduction of immunosuppressive cytokines, leading to an increase in anti-tumor immunity and enhanced survival.

Higher education in South Africa has focused extensively on widening access to further inclusivity and to economic development. However, as students need to persist and succeed in their studies, access alone is not enough. Furthermore, the responsibility of higher education to help students succeed does not end with graduation; institutions need to produce graduates who are ready to enter the labour market. Therefore, it is important to integrate career information and concepts into these practices when conceptualising holistic academic advising. Since academic advising is still developing as a professional practice in the South African context, no clear, practical framework has been used uniformly at universities. Career advice is also not necessarily integrated into academic advising in a conscious manner. This may result in students who are struggling to integrate all the academic and career information provided to make informed decisions regarding their studies and career paths. This paper argues that the 3-I Process is an appropriate framework for the integration of career and academic advising in the South African context. In this case study, we draw from the experiences of nine advisors from the central advising office, faculties, and the career office at the University of the Free State to understand the extent to which they have been incorporating the elements of the 3-I Process into their existing academic advising practices and how they view the possibilities of following a more integrated approach. We also map how the framework can be adapted to the broader South African context to inform and develop more holistic and professionalised advising practices, as well as to contribute towards students' success beyond university.

ABSTRACT Coccidioidomycosis, also known as Valley fever, is a disease caused by the fungal pathogen Coccidioides. Unfortunately, patients are often misdiagnosed with bacterial pneumonia, leading to inappropriate antibiotic treatment. The soil Bacillus subtilis-like species exhibits antagonistic properties against Coccidioides in vitro; however, the antagonistic capabilities of host microbiota against Coccidioides are unexplored. We sought to examine the potential of the tracheal and intestinal microbiomes to inhibit the growth of Coccidioides in vitro. We hypothesized that an uninterrupted lawn of microbiota obtained from antibiotic-free mice would inhibit the growth of Coccidioides, while partial in vitro depletion through antibiotic disk diffusion assays would allow a niche for fungal growth. We observed that the microbiota grown on 2×GYE (GYE) and Columbia colistin and nalidixic acid with 5% sheep’s blood agar inhibited the growth of Coccidioides, but microbiota grown on chocolate agar did not. Partial depletion of the microbiota through antibiotic disk diffusion revealed diminished inhibition and comparable growth of Coccidioides to controls. To characterize the bacteria grown and identify potential candidates contributing to the inhibition of Coccidioides, 16S rRNA sequencing was performed on tracheal and intestinal agar cultures and murine lung extracts. We found that the host bacteria likely responsible for this inhibition primarily included Lactobacillus and Staphylococcus. The results of this study demonstrate the potential of the host microbiota to inhibit the growth of Coccidioides in vitro and suggest that an altered microbiome through antibiotic treatment could negatively impact effective fungal clearance and allow a niche for fungal growth in vivo.IMPORTANCECoccidioidomycosis is caused by a fungal pathogen that invades the host lungs, causing respiratory distress. In 2019, 20,003 cases of Valley fever were reported to the CDC. However, this number likely vastly underrepresents the true number of Valley fever cases, as many go undetected due to poor testing strategies and a lack of diagnostic models. Valley fever is also often misdiagnosed as bacterial pneumonia, resulting in 60%–80% of patients being treated with antibiotics prior to an accurate diagnosis. Misdiagnosis contributes to a growing problem of antibiotic resistance and antibiotic-induced microbiome dysbiosis; the implications for disease outcomes are currently unknown. About 5%–10% of symptomatic Valley fever patients develop chronic pulmonary disease. Valley fever causes a significant financial burden and a reduced quality of life. Little is known regarding what factors contribute to the development of chronic infections and treatments for the disease are limited.

Waste is an increasing global environmental issue. South Africa’s informal sector plays a crucial role in diverting recyclables from landfills. Despite their indispensable contributions, informal recyclers form part of a societal group that is marginalised, negatively labelled and deemed ‘disposable’ under neoliberal capitalist structures. This article draws on data from interviews held with 21 participants who work in the informal recycling sector in Gqeberha (formerly Port Elizabeth) in South Africa. It investigates the participants’ own perceptions of their societal role, of which four became prominent, namely: (1) cleaners of the environment, (2) providers for dependents, (3) informal environmental educators and (4) community uplifters. We argue that the participants’ positive self-views can be seen as a powerful counter-narrative that challenges harmful prevailing stereotypes, which allows for a more nuanced perception of their lives and labour. Their positive self-perceptions and resourcefulness should not be interpreted as an endorsement of neoliberal capitalism that compels them to actively combat stigmatisation. Instead, their determination to resist negative stereotypes simultaneously underscores the necessity of confronting stigmatisation in society. Transdisciplinary contribution: The parallel themes of agency and autonomy in both informal recycling and entrepreneurship prompt a reconsideration of the conventional entrepreneurial discourse and its applicability to marginalised communities. We recommend that informal recyclers’ accumulated knowledge, skill set and well-being be acknowledged to ensure their dignity and that their labour is valued.

Diabetes mellitus (DM) and osteoarthritis (OA) are commonly known metabolic diseases that affect a large segment of the world population. These two conditions share several risk factors such as obesity and aging; however, there is still no consensus regarding the direct role of DM on OA development and progression. Interestingly, both animal and human studies have yielded conflicting results, with some showing a significant role for DM in promoting OA, while others found no significant interactions between these conditions. In this review, we will discuss preclinical and clinical data that assessed the interaction between DM and OA. We will also discuss possible mechanisms associated with the effect of high glucose on the articular cartilage and chondrocytes. An emerging theme dominates the breath of published work in this area: most of the studies discussed in this review do not take into consideration the role of other factors such as the type of diabetes, age, biological sex, type of animal model, body mass index, and the use of pain medications when analyzing and interpreting data. Therefore, future studies should be more rigorous when designing experiments looking at DM and its effects on OA and should carefully account for these confounding factors, so that better approaches can be developed for monitoring and treating patients at risk of OA and DM. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Type 1 diabetes mellitus (T1DM) affects 9.5% of the population. T1DM is characterized by severe insulin deficiency that causes hyperglycemia and leads to several systemic effects. T1DM has been suggested as a risk factor for articular cartilage damage and loss, which could expedite the development of osteoarthritis (OA). OA represents a major public health challenge by affecting 300 million people globally, yet very little is known about the correlation between T1DM and OA. In addition, current studies that have looked at the interaction between diabetes mellitus and OA have reported conflicting results with some suggesting a positive correlation whereas others did not. In this study, we aimed to evaluate whether T1DM exacerbates the development of spontaneous OA or accelerates the progression of posttraumatic osteoarthritis (PTOA) after joint injury. Histological evaluation of T1DM and control joints determined that T1DM mice displayed cartilage degeneration measurements consistent with mild OA phenotypes. RNA sequencing analyses identified significantly upregulated genes in T1DM corresponding to matrix-degrading enzymes known to promote cartilage matrix degradation, suggesting a role of these enzymes in OA development. Next, we assessed whether preexisting T1DM influences PTOA development subsequent to trauma. At 6 weeks post-injury, T1DM injured joints displayed significantly less cartilage damage and joint degeneration than injured non-diabetic joints, suggesting a significant delay in PTOA disease progression. At the single-cell resolution, we identified increased number of cells expressing the chondrocyte markers Col2a1, Acan, and Cytl1 in the T1DM injured group. Our findings demonstrate that T1DM can be a risk factor for OA but not for PTOA. This study provides the first account of single-cell resolution related to T1DM and the risk for OA and PTOA. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

We previously showed that femur fracture in mice caused a reduction in bone volume at distant skeletal sites within 2 weeks post-fracture. Osteocytes also have the ability to remodel their surrounding bone matrix through perilacunar/canalicular remodeling (PLR). If PLR is altered systemically following fracture, this could affect bone mechanical properties and increase fracture risk at all skeletal sites. In this study, we investigated whether lacunar-canalicular microstructure and the rate of PLR are altered in the contralateral limb following femoral fracture in mice. We hypothesized that femoral fracture would accelerate PLR by 2 weeks postfracture, followed by partial recovery by 4 weeks. We used histological evaluation and high-resolution microcomputed tomography to quantify the morphology of the lacunar-canalicular network at the contralateral tibia, and we used quantitative real-time polymerase chain reaction (RT-PCR) and RNA-seq to measure the expression of PLR-associated genes in the contralateral femur. We found that at both 2 and 4 weeks postfracture, canalicular width was significantly increased by 18.6% and 16.6%, respectively, in fractured mice relative to unfractured controls. At 3 days and 4 weeks post-fracture, we observed downregulation of PLR-associated genes; RNA-seq analysis at 3 days post-fracture showed a deceleration of bone formation and mineralization in the contralateral limb. These data demonstrate notable canalicular changes following fracture that could affect bone mechanical properties. These findings expand our understanding of systemic effects of fracture and how biological and structural changes at distant skeletal sites may contribute to increased fracture risk following an acute injury.

The overuse of antibiotics in clinical and livestock settings is accelerating the selection of multidrug resistant bacterial pathogens. Antibiotic resistant bacteria result in increased mortality and financial strain on the health care and livestock industry. The development of new antibiotics has stalled, and novel strategies are needed as we enter the age of antibiotic resistance. Certain naturally occurring clays have been shown to have antimicrobial properties and kill antibiotic resistant bacteria. Harnessing the activity of compounds within these clays that harbor antibiotic properties offers new therapeutic opportunities for fighting the potentially devastating effects of the post antibiotic era. However, natural samples are highly heterogenous and exhibit variable antibacterial effectiveness, therefore synthesizing minerals of high purity with reproducible antibacterial activity is needed. Here we describe for the first time synthetic smectite clay minerals and Fe-sulfide microspheres that reproduce the geochemical antibacterial properties observed in natural occurring clays. We show that these mineral formulations are effective at killing the ESKAPE pathogens (Enterococcus sp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter sp., Pseudomonas aeruginosa and Enterobacter sp.) by maintaining Fe2+ solubility and reactive oxygen species (ROS) production while buffering solution pH, unlike the application of metals alone. Our results represent the first step in utilizing a geochemical process to treat antibiotic resistant topical or gastrointestinal infections in the age of antibiotic resistance.

Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days in vitro), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this in vitro study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity.