Mutations in the parkin gene, which encodes a ubiquitin ligase, are currently recognized as the main contributor to familial forms of Parkinson's disease (PD). A simple assumption about the effects ...of PD‐linked mutations in parkin is that they impair or ablate the enzyme activity. However, a number of recent studies, including ours, have indicated that many disease‐linked point mutants of parkin retain substantial catalytic activity. To understand how the plethora of mutations on parkin contribute to its dysfunction, we have conducted a systematic analysis of a significant number of parkin point mutants (22 in total), which represent the majority of parkin missense/nonsense mutations reported to date. We found that more than half of these mutations, including many located outside of the parkin RING fingers, produce alteration in the solubility of parkin which influences its detergent extraction property. This mutation‐mediated alteration in parkin solubility is also associated with its propensity to form intracellular, aggresome‐like, protein aggregates. However, they do not represent sites where parkin substrates become sequestered. As protein aggregation sequesters the functional forms away from their normal sites of action, our results suggest that alterations in parkin solubility and intracellular localization may underlie the molecular basis of the loss of function caused by several of its mutations.
The performance of adult stem cells is crucial for tissue homeostasis but their regenerative capacity declines with age, leading to failure of multiple organs. In skeletal muscle this failure is ...manifested by the loss of functional tissue, the accumulation of fibrosis, and reduced satellite cell-mediated myogenesis in response to injury. While recent studies have shown that changes in the composition of the satellite cell niche are at least in part responsible for the impaired function observed with aging, little is known about the effects of aging on the intrinsic properties of satellite cells. For instance, their ability to repair DNA damage and the effects of a potential accumulation of DNA double strand breaks (DSBs) on their regenerative performance remain unclear. This work demonstrates that old muscle stem cells display no significant accumulation of DNA DSBs when compared to those of young, as assayed after cell isolation and in tissue sections, either in uninjured muscle or at multiple time points after injury. Additionally, there is no significant difference in the expression of DNA DSB repair proteins or globally assayed DNA damage response genes, suggesting that not only DNA DSBs, but also other types of DNA damage, do not significantly mark aged muscle stem cells. Satellite cells from DNA DSB-repair-deficient SCID mice do have an unsurprisingly higher level of innate DNA DSBs and a weakened recovery from gamma-radiation-induced DNA damage. Interestingly, they are as myogenic in vitro and in vivo as satellite cells from young wild type mice, suggesting that the inefficiency in DNA DSB repair does not directly correlate with the ability to regenerate muscle after injury. Overall, our findings suggest that a DNA DSB-repair deficiency is unlikely to be a key factor in the decline in muscle regeneration observed upon aging.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Population ageing and community care on older adults, as well as the marked social inequalities in health, have received growing concern by the government and the community. This ...study evaluated the medico-social integrated day care model of the Cadenza Hub for older adults with dementia. We also examined whether services subsidized by the publicly funded graded financial support of the Community Care Service Voucher for the Elderly (CCSV) could mitigate social inequalities in community care needs, from the perspective of the caregivers.
Methods
In this qualitative case study, we adopted purposeful sampling strategy to recruit 14 caregivers of active day care service users with dementia, with different socioeconomic background and duration of service use, for face-to-face semi-structured in-depth interviews between June and August 2021. The transcribed data were closely read to capture key themes using thematic analyses.
Results
Caregivers faced tremendous caregiving burden in the absence of community care support and struggled in choosing care services. Most informants benefited from the day care service, whereas the financial support of CCSV was crucial to ensure equitable access to community care. Non-governmental organizations and social workers were the key to bridging the information gap.
Conclusion
The integrated day care of the Cadenza Hub appeared to have addressed the unmet needs of older adults with dementia and their caregivers, including the socioeconomically disadvantaged with the CCSV support. The community care service delivery model might be applicable to address other health inequalities problems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) ...on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells' ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells' capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells' ability to evade NK immunosurveillance and developed an approach to break this interaction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mayaro virus (MAYV) of the genus alphavirus is a mosquito-transmitted emerging infectious disease that causes an acute febrile illness, rash, headaches, and nausea that may turn into incapacitating, ...persistent arthralgias in some victims. Since its discovery in Trinidad in 1954, cases of MAYV infection have largely been confined there and to the northern countries of South America, but recently, MAYV cases have been reported in some island nations in the Caribbean Sea. Accompanying these reports is evidence that new vectors, including Aedes spp. mosquitos, recently implicated in the global spread of Zika and chikungunya viruses, are competent for MAYV transmission, which, if true, could facilitate the spread of MAYV beyond its current range. Despite its status as an emerging virus, there are no licensed vaccines to prevent MAYV infection nor therapeutics to treat it. Here, we describe the development and testing of a novel DNA vaccine, scMAYV-E, that encodes a synthetically-designed consensus MAYV envelope sequence. In vivo electroporation-enhanced immunization of mice with this vaccine induced potent humoral responses including neutralizing antibodies as well as robust T-cell responses to multiple epitopes in the MAYV envelope. Importantly, these scMAYV-E-induced immune responses protected susceptible mice from morbidity and mortality following a MAYV challenge.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Eastern Australia recently experienced an intense drought (Millennium Drought, 2003–2009) and record‐breaking rainfall and flooding (austral summer 2010–2011). There is some limited evidence for a ...climate change contribution to these events, but such analyses are hampered by the paucity of information on long‐term natural variability. Analyzing a new reconstruction of summer (December–January–February) Palmer Drought Severity Index (the Australia‐New Zealand Drought Atlas; ANZDA, 1500–2012 Common Era), we find moisture deficits during the Millennium Drought fall within the range of the last 500 years of natural hydroclimate variability. This variability includes periods of multidecadal drought in the 1500s more persistent than any event in the historical record. However, the severity of the Millennium Drought, which was caused by autumn (March‐April‐May) precipitation declines, may be underestimated in the ANZDA because the reconstruction is biased toward summer and antecedent spring (September‐October‐November) precipitation. The pluvial in 2011, however, which was characterized by extreme summer rainfall faithfully captured by the ANZDA, is likely the wettest year in the reconstruction for Coastal Queensland. Climate projections (Representative Concentration Pathways (RCP) 8.5 scenario) suggest that eastern Australia will experience long‐term drying during the 21st century. While the contribution of anthropogenic forcing to recent extremes remains an open question, these projections indicate an amplified risk of multiyear drought anomalies matching or exceeding the intensity of the Millennium Drought.
Key Points
Recent extremes (the Millennium Drought and 2011 pluvial) are compared to a 500‐year soil moisture reconstruction
2011 was likely the wettest year in the record for Coastal Queensland
Climate projections indicate substantially increased risk of droughts ≥ the magnitude of the Millennium Drought
In 2014, ASTIGU - a Japanese pantyhose brand - launched 'ashi wa, kao' (legs are face), a new series of advertisements featuring a female model whose face is painted black. Although scholars have ...previously written on blackface and blackness in Japan, they have focused more on subcultural contexts and men's instead of women's experiences. Drawing on the campaign's promotional materials and employing women's blackface practices as a heuristic device, this essay tracks constructions of blackness and femininity in Japanese advertising. I argue that Japanese women's wearing of blackface forms affective spaces for consumers to negotiate their racial, gender, and national identities. While 'Japaneseness' and femininity are initially based on the bihaku (beautiful white) model, the idea of black masks alters women's relationships to their bodies and allows them to experiment with racial otherness and alternative femininities. By unsettling notions of race, gender, and nation in Japanese society, I suggest that the dual commodification of bihaku and blackface in these advertisements potentially generates transnational forms of femininity. Building on scholarship on race, affect, femininity, and Japanese mass culture, this essay ultimately investigates how consuming women in blackface traverses gender and racial constructions in Japan, contributing to transnational flows of consumer culture.
Powassan virus (POWV) infection is a tick-borne emerging infectious disease in the United States and North America. Like Zika virus, POWV is a member of the family Flaviviridae. POWV causes severe ...neurological sequalae, meningitis, encephalitis, and can cause death. Although the risk of human POWV infection is low, its incidence in the U.S. in the past 16 years has increased over 300%, urging immediate attention. Despite the disease severity and its growing potential for threatening larger populations, currently there are no licensed vaccines which provide protection against POWV. We developed a novel synthetic DNA vaccine termed POWV-SEV by focusing on the conserved portions of POWV pre-membrane and envelope (prMEnv) genes. A single immunization of POWV-SEV elicited broad T and B cell immunity in mice with minimal cross-reactivity against other flaviviruses. Antibody epitope mapping demonstrated a similarity between POWV-SEV-induced immune responses and those elicited naturally in POWV-infected patients. Finally, POWV-SEV induced immunity provided protection against POWV disease in lethal challenge experiments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
3D printing is a popular technology in many industries secondary to its ability to rapidly produce inexpensive, high fidelity models/products, mainly through layer-by-layer fusion of ...various substrate materials. In healthcare, 3D printing has garnered interest for its applications in surgery, simulation, education, and medical device development, and 3D printing facilities are now being integrated into hospital-based settings. Yet, little is known regarding the leadership, resources, outputs, and role of these new onsite entities.
Methods
The purpose of this research was to survey features of North American hospital-based 3D printing facilities to understand their design and utility in anticipation of future expansion. Hospital-based 3D printing labs were recruited through online special interest groups to participate via survey response. Anonymous, voluntary data were collected from 21 facilities over 9 weeks and reported/analyzed in aggregate.
Results
Of the respondents, > 50% were founded in the past 5 years and 80% in the past decade, indicating recent and rapid growth of such facilities. Labs were most commonly found within large, university-affiliated hospitals/health systems with administration frequently, but not exclusively, through radiology departments, which was shown to enhance collaboration. All groups reported collaborating with other medical specialties/departments and image segmentation as part of the workflow, showing widespread interest in high fidelity, personalized medicine applications. Lab leadership was most often multidisciplinary, with physicians present on nearly all leadership teams. Budgets, personnel, and outputs varied among groups, however, all groups reported engagement in multiple 3D printing applications.
Conclusion
This preliminary study provides a foundation for understanding the unique nature of hospital-based 3D printing labs. While there is much to learn about such in-house facilities, the data obtained reveal important baseline characteristics. Further research is indicated to validate these early findings and create a detailed picture of the developing infrastructure of 3D printing in healthcare settings.
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