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Background: Music has long been identified as a nonpharmacological tool that can provide benefits for people with dementia, and there is considerable interest in designing technologies to support the use of music in dementia care. However, to ensure that music technologies are appropriately designed for supporting caregivers and people living with dementia, there remains a need to better understand how music is currently used in everyday dementia care at home., Objective: This study aims to understand how people living with dementia and their caregivers use music and music technologies in everyday caring, as well as the challenges they experience using music and technology., Methods: This study used a mixed methods design. First, a survey was administered to 13 people living with dementia and 64 caregivers to understand their use of music and technology. Subsequently, 18 survey respondents (family caregivers: n=12, 67%; people living with dementia: n=6, 33%) participated in focus groups regarding their experiences of using music and technology in care. Interview transcripts were analyzed using reflexive thematic analysis., Results: Most of the survey respondents (people living with dementia: 9/13, 69%; family caregivers: 47/63, 75%) reported using music often or very often in their daily lives. Participants reported a range of technologies used for listening to music, such as CDs, radio, and streaming services. Focus groups highlighted the benefits and challenges of using music and music technologies in everyday care. Participants identified using music and music technologies to regulate mood, provide joy, facilitate social interaction and connection, encourage reminiscence, provide continuity of music use before and after the dementia diagnosis, and make caregiving easier. The challenges of using music technology in everyday caring included difficulties with staying up to date with evolving technology and low self-efficacy with technology for people living with dementia., Conclusions: This study shows that people with a dementia diagnosis and their caregivers already use music and music technologies to support their everyday care needs. The results suggest opportunities to design technologies that enable easier access to music and to support people living with dementia with recreational and therapeutic music listening as well as music-based activities., (©Dianna Vidas, Romina Carrasco, Ryan M Kelly, Jenny Waycott, Jeanette Tamplin, Kate McMahon, Libby M Flynn, Phoebe A Stretton-Smith, Tanara Viera Sousa, Felicity A Baker. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 27.08.2024.)

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition with a constellation of symptoms presenting as severe and profound fatigue of ≥ 6 months not relieved by rest. ME/CFS affects health-related quality of life (HRQoL), which can be measured using multi-attribute health state utility (HSU) instruments. The aims of this study were to quantify HSUs for people living with ME/CFS, and to identify an instrument that is preferentially sensitive for ME/CFS., Methods: Cross-sectional national survey of people with ME/CFS using the AQoL-8D and EQ-5D-5L. Additional questions from the AQoL-8D were used as 'bolt-ons' to the EQ-5D-5L (i.e., EQ-5D-5L-Psychosocial). Disability and fatigue severity were assessed using the De Paul Symptom Questionnaire-Short Form (DSQ-SF). HSUs were generated using Australian tariffs. Mean HSUs were stratified for sociodemographic and clinical factors. Bland-Altman plots were used to compare the three HSU instruments., Results: For the 198 participants, mean HSUs (95% confidence intervals) were EQ-5D-5L: 0.46 (0.42-0.50); AQoL-8D: 0.43 (0.41-0.45); EQ-5D-5L-Psychosocial: 0.44 (0.42-0.46). HSUs were substantially lower than population norms: EQ-5D-5L: 0.89; AQoL-8D: 0.77. As disability and fatigue severity increased, HSUs decreased in all three instruments. Bland-Altman plots revealed interchangeability between the AQoL-8D and EQ-5D-5LPsychosocial. Floor and ceiling effects of 13.5% and 2.5% respectively were observed for the EQ-5D-5L instrument only., Conclusions: ME/CFS has a profound impact on HRQoL. The AQoL-8D and EQ-5D-5L-Psychosocial can be used interchangeably: the latter represents a reduced participant burden., (© 2023. The Author(s).)

Objective This study aimed to estimate costs of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to patients, government and Australian society. Methods Australian ME/CFS patients and their carers were recruited using convenience sampling. Patients completed an online retrospective cost diary, providing ME/CFS-related direct medical, non-medical and indirect costs. Informal care costs were collected directly from carers. Data from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule were linked to participant survey data. Annual per patient and total societal costs were estimated, broken down by category and presented in 2021 AUD. Factors associated with higher costs were investigated using generalised linear models. Results One hundred and seventy five patients (mean age 49 years s.d. 14, 79.4% female) completed the cost diary. Estimated total annual societal costs of ME/CFS in Australia ranged between $1.38 and $10.09 billion, with average annual total costs of $63 400/patient. Three-quarters of these costs were due to indirect costs ($46 731). Disability severity was the key factor associated with higher costs, particularly for indirect costs (being 2.27-fold higher for severe disability than no/mild disability). Conclusions ME/CFS poses a significant economic burden in Australia, owing mainly to high indirect and informal care costs.

Background: Lockdowns have been used to prevent the spread of transmissible illnesses such as influenza, norovirus, and COVID-19 in care homes. However, lockdowns deny care home residents supplemental care and the socioemotional enrichment that comes from seeing family members. Video calling has the potential to enable ongoing contact between residents and family members during lockdowns. However, video calls can be considered by some as a poor substitute for in-person visits. It is important to understand family members' experiences with video calling during lockdowns to ensure the effective use of this technology in the future., Objective: This study aimed to understand how family members use video calls to communicate with relatives living in aged care during lockdowns. We focused on experiences during the COVID-19 pandemic, which involved extensive lockdowns in aged care homes., Methods: We conducted semistructured interviews with 18 adults who had been using video calls with relatives living in aged care during pandemic lockdowns. The interviews focused on how participants had been using video calls, what benefits they gained from video-based interactions, and what challenges they encountered when using the technology. We analyzed the data using the 6-phase reflexive approach to thematic analysis by Braun and Clarke., Results: We developed 4 themes through our analysis. Theme 1 interprets video calling as a medium for the continuation of care during lockdowns. Using video calls, family members were able to provide social enrichment for residents and engaged in health monitoring to uphold residents' welfare. Theme 2 highlights how video calling extended care by supporting frequent contact, transmitting nonverbal cues that were essential for communication, and negating the need for face masks. Theme 3 interprets organizational issues such as the lack of technology and staff time as impediments to the continuation of familial care through video. Finally, theme 4 highlights the need for 2-way communication, interpreting residents' unfamiliarity with video calling and their health conditions as further barriers to the continuation of care., Conclusions: This study suggests that, during restrictions arising from the COVID-19 pandemic, video calls became a medium for enabling family members to continue participating in the care of their relatives. The use of video calls to continue care illustrates their value for families during times of mandatory lockdown and supports the use of video to complement face-to-face visits at other times. However, better support is needed for video calling in aged care homes. This study also revealed a need for video calling systems that are designed for the aged care context., (©Ryan M Kelly, Yushan Xing, Steven Baker, Jenny Waycott. Originally published in JMIR Aging (https://aging.jmir.org), 12.06.2023.)

Background: Digital technologies such as virtual reality (VR), humanoid robots, and digital companion pets have the potential to provide social and emotional enrichment for people living in aged care. However, there is currently limited knowledge about how technologies are being used to provide enrichment, what benefits they provide, and what challenges arise when deploying these technologies in aged care settings., Objective: This study aims to investigate how digital technologies are being used for social and emotional enrichment in the Australian aged care industry and identify the benefits and challenges of using technology for enrichment in aged care., Methods: A web-based survey (N=20) was distributed among people working in the Australian aged care sector. The survey collected information about the types of technologies being deployed and their perceived value. The survey was followed by semistructured interviews (N=12) with aged care workers and technology developers to investigate their experiences of deploying technologies with older adults living in aged care. Survey data were analyzed using summary descriptive statistics and categorizing open-ended text responses. Interview data were analyzed using reflexive thematic analysis., Results: The survey revealed that a range of commercial technologies, such as VR, tablet devices, and mobile phones, are being used in aged care to support social activities and provide entertainment. Respondents had differing views about the value of emerging technologies, such as VR, social robots, and robot pets, but were more united in their views about the value of videoconferencing. Interviews revealed 4 types of technology-mediated enrichment experiences: enhancing social engagement, virtually leaving the care home, reconnecting with personal interests, and providing entertainment and distraction. Our analysis identified 5 barriers: resource constraints, the need to select appropriate devices and apps, client challenges, limited staff and organizational support, and family resistance., Conclusions: This study demonstrates that technologies can be used in aged care to create personally meaningful enrichment experiences for aged care clients. To maximize the effectiveness of technology-mediated enrichment, we argue that a person-centered care approach is crucial. Although enrichment experiences can be created using available technologies, they must be carefully selected and co-deployed with aged care clients. However, significant changes may be required within organizations to allow caregivers to facilitate individual technology-based activities for enrichment., (©Jenny Waycott, Wei Zhao, Ryan M Kelly, Elena Robertson. Originally published in JMIR Aging (https://aging.jmir.org), 12.04.2022.)

Rice busk biochar was mixed with cobalt (Co)-polluted soil to examine the efficacy of biochar for Co immobilization and detoxification in fluvo-aquic soil. The Co speciation (modified BCR sequential extraction), fluorescein diacetate (FDA) hydrolysis and soil enzyme activities were investigated. In soil, the Co ions (acid-soluble fraction) could be uptake by biochar due to the microporous structure on the surface, as well as the oxygen-containing functional groups and conjugated structure in the molecular structure. Therefore, when the biochar concentration was lower than the optimum concentration (~6 g·kg -1 ), there was transformation of Co from the acid-soluble fraction to the oxidizable fraction, resulting in lower environmental risk. However, if the biochar concentration continued increasing, the distribution coefficient of Co in the acid-soluble fraction increased (P < 0.05). The biochar could also reduce the toxicity of Co, resulting in the negative correlations between soil enzyme activities (FDA hydrolysis, urease and alkaline phosphatases) and Co in the acid-soluble fraction (r = -0.816, -0.928 and -0.908, respectively, P < 0.01). When the biochar concentration ranged from 5.83 to 6.76 g·kg -1 , the efficacy for Co immobilization and detoxification reached the maxima. To conclude, in fluvo-aquic soil, rice busk biochar is an effective amendment for immobilizing Co ions and reducing the toxicity of Co. The biochar concentration in soil should range from 5.83 to 6.76 g·kg -1 to reach the optimum efficacy.

Environmentally friendly acid-leaching processes with three organic acids (maleic, glycolic and acetoacetic) were developed to recover valuable metals from the cathodic material of spent lithium-ion batteries (LiCoO 2 ). The leaching efficiencies of Li and Co by the maleic acid were 99.58% and 98.77%, respectively. The leaching efficiencies of Li and Co by the glycolic acid were 98.54% and 97.83%, while those by the acetoacetic acid were 98.62% and 97.99%, respectively. The optimal acid concentration for the maleic acid-, glycolic acid- and acetoacetic acid-leaching processes were 1, 2 and 1.5 mol l -1 , respectively, while their optimal H 2 O 2 concentrations were 1.5, 2 and 1.5 vol%, respectively. The optimal solid/liquid ratio, temperature and reaction time for the leaching process of the three organic acids was the same (10 g l -1 , 70°C, 60 min). The thermodynamic formation energy of the leaching products and the Gibbs free energy of the leaching reactions were calculated, and the kinetic study showed that the leaching processes fit well with the shrinking-core model. Based on the comparison in the leaching parameters, the efficacy and availability of the three acids is as follows: maleic acid > acetoacetic acid > glycolic acid., Competing Interests: We have no competing interests., (© 2019 The Authors.)

Several postmortem studies have reported lower levels of immunoreactivity (IR) for microtubule-associated protein 2 (MAP2) in several cortical regions of individuals with schizophrenia (SZ). However, whether this effect is conserved across multiple brain areas within an individual with SZ or if it is regionally-specific remains unclear. We characterized patterns of MAP2-IR across three cortical regions at different levels of the rostral-caudal axis within individual subjects with and without SZ. MAP2-IR levels were measured in deep layer 3 of dorsolateral prefrontal cortex (DLPFC), lateral intraparietal cortex (LIP), and primary visual cortex (V1). Postmortem tissue containing each cortical region was derived from 20 pairs of SZ subjects and nonpsychiatric comparison (NPC) subjects matched perfectly for sex, and as closely as possible for age and postmortem interval. MAP2-IR was assessed by quantitative fluorescence microscopy. We observed significantly lower levels of MAP2-IR in SZ subjects relative to NPC subjects, without a significant region by diagnosis interaction. Logs of the within-pair ratios (SZ:NPC) of MAP2-IR were significantly correlated across the three regions. These findings demonstrate that MAP2-IR deficits in SZ are consistent across three neocortical regions within individual subjects. This pattern of MAP2-IR deficit has implications for therapeutic development and future investigations of MAP2 pathology in SZ.

High incident rates of red tide have occurred off the coast of the Changjiang (Yangtze) River Estuary in summer, resulting from a magnified population growth discharging substantial nutrient loads into this vicinity. The presence of elevated Chlorophyll-a concentrations (≥36.3 μg/l), low suspended sediment concentrations in surface and mid-layers (<10 mg/l), a strong saline front and surface water temperature gradient, veering surface winds, and a bimodal shape to the Changjiang Diluted Water (CDW) revealed two red tide patches appearing between August 6-13, 2010. Two distinguishable hydrodynamic driving mechanisms, connected to these incidents, are diagnosed. Field observations and numerical simulations determined a red tide patch in the northeastern offshore area is caused by a northeast transport of the CDW truncated by a northwest intrusion of the Taiwan Warm Current (TWC) as winds deviated. Red tide occurrence in the southern nearshore area originated from a plume front where CDW interfaces with the TWC., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Previously, we demonstrated that dendritic spine density (DSD) in deep layer 3 of the primary auditory cortex (A1) is lower, due to having fewer small spines, in subjects with schizophrenia (SZ) than non-psychiatric control (NPC) subjects. We also previously demonstrated that microtubule-associated-protein-2 immunoreactivity (MAP2-IR) in A1 deep layer 3 is lower, and positively correlated with DSD, in SZ subjects. Here, we first sought to confirm these findings in an independent cohort of 25 SZ-NPC subject pairs (cohort 1). We used immunohistochemistry and confocal microscopy to measure DSD and MAP2-IR in A1 deep layer 3. Consistent with previous studies, both DSD and MAP2-IR were lower in SZ subjects. We then tested the hypothesis that MAP2-IR mediates the effect of SZ on DSD in a cohort of 45 SZ-NPC subject pairs (combined cohort) that included all subjects from cohort 1 and two previously studied cohorts. Based on the distribution of MAP2-IR values in NPC subjects, we categorized each SZ subject as having either low MAP2-IR (SZ MAP2-IR(low)) or normal MAP2-IR (SZ MAP2-IR(normal)). Among SZ MAP-IR(low) subjects, mean DSD was significantly lower than in NPC subjects. However, mean DSD did not differ between SZ MAP2-IR(normal) and NPC subjects. Moreover, MAP2-IR statistically mediated small spine differences, with lower MAP2-IR values associated with fewer small spines. Our findings confirm that low density of small spines and low MAP2-IR are robust SZ phenotypes and suggest that MAP2-IR mediates the effect of SZ on DSD.

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the elongated G1 phase of the cell cycle during aging may actually play an important role in allowing aged cells time to repair accumulating DNA damage.

The cytokine IL-2 is critical for promoting the development, homeostasis, and function of regulatory T (Treg) cells. The cellular sources of IL-2 that promote these processes remain unclear. T cells, B cells, and dendritic cells (DCs) are known to make IL-2 in peripheral tissues. We found that T cells and DCs in the thymus also make IL-2. To identify cellular sources of IL-2 in Treg cell development and homeostasis, we used Il2 FL/FL mice to selectively delete Il2 in T cells, B cells, and DCs. Because IL-15 can partially substitute for IL-2 in Treg cell development, we carried out the majority of these studies on an Il15 -/- background. Deletion of Il2 in B cells, DCs, or both these subsets had no effect on Treg cell development, either in wild-type (WT) or Il15 -/- mice. Deletion of Il2 in T cells had minimal effects in WT mice but virtually eliminated developing Treg cells in Il15 -/- mice. In the spleen and most peripheral lymphoid organs, deletion of Il2 in B cells, DCs, or both subsets had no effect on Treg cell homeostasis. In contrast, deletion of Il2 in T cells led to a significant decrease in Treg cells in either WT or Il15 -/- mice. The one exception was the mesenteric lymph nodes where significantly fewer Treg cells were observed when Il2 was deleted in both T cells and DCs. Thus, T cells are the sole source of IL-2 needed for Treg cell development, but DCs can contribute to Treg cell homeostasis in select organs., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The distribution of pollutants in waste clay bricks from an organochlorine pesticide-contaminated site was investigated, and removal of the pollutants using a thermal desorption technology was studied. The results showed that the contents of HCHs in both the surface and the inner layer of the bricks were slightly higher than those of DDTs. The total pore volume of the bricks was 37.7 to 41.6% with an increase from external to internal surfaces. The removal efficiency by thermal treatment was within 62 to 83% for HCHs and DDTs in bricks when the temperature was raised from 200 to 250 °C after 1 h. HCHs were more easily removed than DDTs with a higher temperature. Either intraparticle or surface diffusion controls the desorption processes of pollutants in bricks. It was feasible to use the polluted bricks after removal of the pollutants by low-temperature thermal desorption technology.

Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.

Objective: Decreased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large or mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. Here, the authors examined the density and volume of dendritic spines in deep layer 3 of the auditory cortex of 20 schizophrenia and 20 matched comparison subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss., Method: Primary auditory cortex deep layer 3 spine density and volume was assessed in 20 pairs of schizophrenia and matched comparison subjects in an initial and replication cohort (12 and eight pairs) by immunohistochemistry-confocal microscopy. Targeted mass spectrometry was used to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture., Results: Only the smallest spines are lost in deep layer 3 of the primary auditory cortex in subjects with schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, are inversely correlated with the density of smaller, but not larger, spines in schizophrenia subjects. Consistent with this observation, CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures., Conclusions: These findings require a rethinking of the overpruning hypothesis, demonstrate a link between small spine loss and a schizophrenia risk gene, and should spur more in-depth investigations of the mechanisms that govern new or small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia.

Pale Indian plantain (Arnoglossum atriplicifolium (L.) H. Rob.) is a plant with traditional medicinal usage among the Cherokee Native American tribe for treating cancer. Two oplopane sesquiterpenoids were isolated from an extract of A. atriplicifolium from Western North Carolina. The compounds were isolated by bioassay-guided fractionation using an MCF-7 breast tumour cell line assay. The known compound (1S,6R,7R,8R)-1-acetoxy-6,7-diangeloxy-8,10-epoxy-2-oxo-oplopa-3,14Z,11,12-dien-13-al (1) had an EC50 value of 9.0 μM against MCF-7 cells, while the new compound (1S,3R,6R,7R,8R,11S)-1-acetoxy-6,7-diangeloxy-8,10,11,13-bisepoxyoplopan-2-one (2) had an EC50 value of 96 μM. The compounds were characterised by 1D and 2D NMR spectroscopy and by comparison with literature values in the case for 1. Based on NOESY analysis, a correction of the relative configuration for 1 is presented. The presence of these compounds may help to explain the folk remedy usage of this plant as an anticancer agent.

The immunomodulator FTY720 (FTY) is beneficial in models of graft-versus-host disease, solid organ transplantation, and autoimmunity and has been approved for use in patients with multiple sclerosis. FTY modifies the homing and migration of many cell types. We report that FTY has profound positive and negative effects on allogeneic bone marrow (BM) engraftment in sublethally irradiated recipients. FTY increased donor hematopoietic progenitors in the BM, resulting in high donor engraftment in the B cell, myeloid cell, and natural killer cell, but not T cell, lineages. Donor T cell progenitors within the thymus of FTY-treated recipients were dramatically reduced, resulting in a lack of donor T cell reconstitution. In addition to preventing the ingress of donor (and host) T cell progenitors, FTY prevented the egress of fully functional host CD4+CD8- and CD4-CD8+ thymocytes that on cessation of FTY administration were able to exit from the thymus and contribute to a rapid and complete rejection of a well-established donor BM graft. When used in combination with anti-CD40L mAbs to block the CD40L:CD40 costimulatory pathway, FTY markedly enhanced anti-CD40L mAb-mediated alloengraftment promotion. In contrast to FTY alone, the combination of anti-CD40L mAb and FTY resulted in a surprisingly stable, multilineage, long-term donor chimerism. These data illustrate FTY's profound migration modulating effects and suggest a use in combinatorial therapy in achieving stable alloengraftment under nonmyeloablative conditions., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Myeloablative conditioning before bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T-cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen-induced TEC damage directly contributes to slow thymopoietic recovery after BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given before conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BM transplant recipients. Therefore, we investigated whether the addition of a pharmacologic inhibitor, PFT-beta, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-beta administration additively restored numbers of cortical and medullary TECs and improved thymic function after BMT, resulting in higher numbers of donor-derived, naive peripheral CD4(+) and CD8(+) T cells. Radiation conditioning caused a loss of T-cell zone fibroblastic reticular cells (FRCs) and CCL21 expression in lymphoid stroma. KGF + PFT-beta treatment restored both FRC and CCL21 expression, findings that correlated with improved T-cell reconstitution and an enhanced immune response against Listeria monocytogenes infection. Thus, transient p53 inhibition combined with KGF represents a novel and potentially translatable approach to promote rapid and durable thymic and peripheral T-cell recovery after BMT.

Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells capable of giving rise to a broad range of tissue cells. As such, MAPCs hold promise for tissue injury repair after transplant. In vitro, MAPCs potently suppressed allogeneic T-cell activation and proliferation in a dose-dependent, cell contact-independent, and T-regulatory cell-independent manner. Suppression occurred primarily through prostaglandin E(2) synthesis in MAPCs, which resulted in decreased proinflammatory cytokine production. When given systemically, MAPCs did not home to sites of allopriming and did not suppress graft-versus-host disease (GVHD). To ensure that MAPCs would colocalize with donor T cells, MAPCs were injected directly into the spleen at bone marrow transplantation. MAPCs limited donor T-cell proliferation and GVHD-induced injury via prostaglandin E(2) synthesis in vivo. Moreover, MAPCs altered the balance away from positive and toward inhibitory costimulatory pathway expression in splenic T cells and antigen-presenting cells. These findings are the first to describe the immunosuppressive capacity and mechanism of MAPC-induced suppression of T-cell alloresponses and illustrate the requirement for MAPC colocalization to sites of initial donor T-cell activation for GVHD inhibition. Such data have implications for the use of allogeneic MAPCs and possibly other immunomodulatory nonhematopoietic stem cells for preventing GVHD in the clinic.

Myeloablative conditioning results in thymic epithelial cell (TEC) injury, slow T-cell reconstitution, and a high risk of opportunistic infections. Keratinocyte growth factor (KGF) stimulates TEC proliferation and, when given preconditioning, reduces TEC injury. Thymocytes and TECs express androgen receptors, and exposure to androgen inhibits thymopoiesis. In this study, we have investigated whether TEC stimulation via preconditioning treatment with KGF and leuprolide acetate (Lupron), 2 clinically approved agents, given only before conditioning would circumvent the profound TEC and associated T-cell deficiency seen in allogeneic bone marrow transplant (BMT) recipients. Only combined treatment with KGF plus leuprolide acetate normalized TEC subset numbers and thymic architecture. Thymopoiesis and thymic output were supranormal, leading to the accelerated peripheral reconstitution of naive CD4 and CD8 T cells with a broad Vbeta repertoire and decreased homeostatic T-cell proliferation. Combined therapy facilitated T:B cooperativity and enabled a B-cell humoral response to a CD4 T cell-dependent neoantigen challenge soon after BMT. In vivo antigen-specific CD8 T-cell responses and clearance of a live pathogen was superior with combined versus individual agent therapy. Thus, KGF combined with androgen blockade represents a novel approach to restore thymic function and facilitates the rapid recovery of peripheral T-cell function after allogeneic BMT.

Cryptococcus neoformans is an encapsulated fungal pathogen with a predilection to infect persons with suppressed T-cell function. Cryptococcal mannoproteins (MP) are highly mannosylated antigens which elicit T-cell responses in infected mice and in convalescent patients. Key to the immunogenicity of MP is its capacity to bind to the conserved mannose receptor (MR), CD206, on dendritic cells (DCs). To test the role of the MR in the immune response to C. neoformans, wild-type and MR knockout (MR KO) mice were compared by using in vivo and ex vivo models of cryptococcosis. Following a pulmonary challenge with C. neoformans, MR KO mice died significantly faster than wild-type mice and had higher lung fungal burdens after 4 weeks of infection. Uptake of MP was similar when DCs obtained from wild-type and MR KO mice were compared. Additionally, MP did not upregulate the maturation markers major histocompatibility complex class II, CD86, and CD40 in either wild-type or MR KO DCs. However, MP stimulated lymphoproliferation in CD4(+) T cells obtained from the peripheral lymph nodes of infected wild-type but not MR KO mice. These studies demonstrate a nonredundant role for the MR in the development of CD4(+) T-cell responses to MP and protection from C. neoformans.

The encapsulated pathogenic yeast Cryptococcus neoformans is poorly recognized by phagocytic cells in the absence of opsonins. Macrophages will bind and internalize complement- or antibody-opsonized C. neoformans; however, less is known about the role of opsonins in dendritic cell (DC)-mediated recognition of the organism. Thus, we studied the opsonic requirements for binding to C. neoformans by cultured human monocyte-derived and murine bone marrow-derived DCs and whether binding leads to antifungal activity and cytokine release. Binding of unopsonized C. neoformans to human and murine DCs was negligible. Opsonization with pooled human serum (PHS) increased binding, while heat treatment of PHS virtually abolished this binding, thus suggesting a role for heat-labile complement components. PHS plus a monoclonal anticapsular antibody, 3C2, had an additive effect on binding for most cryptococcal strains. Human and murine DCs exhibited pronounced anticryptococcal activity in the presence of the antibody at early (2-h) and late (24-h) time points; however, PHS opsonization did not supplement this anticryptococcal activity. Antifungal activity against C. neoformans opsonized in PHS and/or antibody was partially reduced in the presence of inhibitors of the respiratory burst response. Human, but not murine, DCs released modest amounts of tumor necrosis factor alpha when stimulated with C. neoformans opsonized in PHS and/or antibody. However, opsonized C. neoformans failed to stimulate detectable release of interleukin 10 (IL-10) or IL-12p70 from either DC population. Thus, human and murine DCs show maximal binding to and antifungal activity against C. neoformans via a process highly dependent on opsonization.