Ultraviolet-C mediated inactivation of Candida auris, a rapid emerging health threat.

Health care-associated infections, particularly those caused by multidrug-resistant organisms (MDROs), pose significant challenges to patient safety. Candida auris (C auris), an emerging MDRO fungus, has been acknowledged as an urgent threat by the Centers for Disease Control and Prevention due to its high mortality and difficulty in prevention, diagnosis, and treatment. In this study, we investigated the efficacy of 254 nm ultraviolet-C light (UV-C) in inactivating C auris on hard surfaces. A mobile UV-C tower equipped with high-performance bulbs was used, and within 7 minutes of continuous exposure, ≥99.97% (≥3.86 log10) inactivation of C auris was achieved in a patient-room-sized test chamber. Our findings suggest that UV-C can serve as an adjunct infection control measure for preventing C auris and other MDRO Health care-associated infections in health care settings. Implementation of UV-C disinfection protocols can contribute to enhanced patient safety and combat the growing threat of MDRO pathogens.

Evaluation of germicidal ultraviolet-C disinfection in a real-world outpatient health care environment.

BACKGROUND: The coronavirus disease 2019 pandemic has highlighted the need for effective infection control in outpatient health care settings. Germicidal ultraviolet-C (GUV) light, known for inactivating microorganisms by damaging their deoxyribonucleic acid or ribonucleic acid, offers a potential solution. This study examines the efficacy of GUV air disinfection systems in real-world outpatient environments. METHODS: We deployed upper-room and far-UV GUV fixtures in 3 outpatient facilities, assessing their impact on bacterial loads through air and surface sampling and bioindicator tests. Occupancy was also monitored. RESULTS: While manual air and surface sampling did not show a significant difference in bacterial loads between control and Ultraviolet C-treated groups, bioindicator tests demonstrated a high level of spore inactivation (up to 99.7% for upper-room GUV and 96.26% for far-UV). Occupancy levels did not significantly influence these outcomes. DISCUSSION: The discrepancy between bioindicator efficacy and environmental sampling results suggests limitations in the latter's ability to accurately capture environmental bioburden. Bioindicators proved to be reliable for in-situ validation of Ultraviolet C surface disinfection. CONCLUSIONS: Bioindicators are effective for validating GUV surface disinfection efficacy in health care settings, though further research is needed to optimize environmental sampling methods for assessing GUV's impact on real-world bacterial loads.

Identification and genome sequencing of an influenza H3N2 variant in wastewater from elementary schools during a surge of influenza A cases in Las Vegas, Nevada.

Real-time surveillance of infectious diseases at schools or in communities is often hampered by delays in reporting due to resource limitations and infrastructure issues. By incorporating quantitative PCR and genome sequencing, wastewater surveillance has been an effective complement to public health surveillance at the community and building-scale for pathogens such as poliovirus, SARS-CoV-2, and even the monkeypox virus. In this study, we asked whether wastewater surveillance programs at elementary schools could be leveraged to detect RNA from influenza viruses shed in wastewater. We monitored for influenza A and B viral RNA in wastewater from six elementary schools from January to May 2022. Quantitative PCR led to the identification of influenza A viral RNA at three schools, which coincided with the lifting of COVID-19 restrictions and a surge in influenza A infections in Las Vegas, Nevada, USA. We performed genome sequencing of wastewater RNA, leading to the identification of a 2021-2022 vaccine-resistant influenza A (H3N2) 3C.2a1b.2a.2 subclade. We next tested wastewater samples from a treatment plant that serviced the elementary schools, but we were unable to detect the presence of influenza A/B RNA. Together, our results demonstrate the utility of near-source wastewater surveillance for the detection of local influenza transmission in schools, which has the potential to be investigated further with paired school-level influenza incidence data.

Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo.

The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα. Extracellular vesicles (EV's) have been implicated in a wide range of functions. However, the functional significance of neural EV's remains to be established. Here we demonstrate that co-expression of CSPα with the disease-associated proteins, polyglutamine expanded protein 72Q huntingtinex°n1 or superoxide dismutase-1 (SOD-1G93A) leads to the cellular export of both 72Q huntingtinex°n1 and SOD-1G93A via EV's. In contrast, the inactive CSPαHPD-AAA mutant does not facilitate elimination of misfolded proteins. Furthermore, CSPα-mediated export of 72Q huntingtinex°n1 is reduced by the polyphenol, resveratrol. Our results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSPα thus represents a potential therapeutic target for neurodegenerative diseases.

J protein mutations and resulting proteostasis collapse.

Despite a century of intensive investigation the effective treatment of protein aggregation diseases remains elusive. Ordinarily, molecular chaperones ensure that proteins maintain their functional conformation. The appearance of misfolded proteins that aggregate implies the collapse of the cellular chaperone quality control network. That said, the cellular chaperone network is extensive and functional information regarding the detailed action of specific chaperones is not yet available. J proteins (DnaJ/Hsp40) are a family of chaperone cofactors that harness Hsc70 (heat shock cognate protein of 70 kDa) for diverse conformational cellular tasks and, as such, represent novel clinically relevant targets for diseases resulting from the disruption of proteostasis. Here we review incisive reports identifying mutations in individual J protein chaperones and the proteostasis collapse that ensues.

δ-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes.

Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, ρ = 0.24, P<10(-4)). A genome-wide association study using 187,657 single nucleotide polymorphisms (SNPs) for the bivariate outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6 × 10(-7)). These SNPs were also significantly associated with bivariate outcomes of CC and scores on several highly heritable neuropsychological tests (5.7 × 10(-9) ≤ P<3.7 × 10(-6)). Statistical interaction was demonstrated between rs17183619 and APP SNP rs2096488 on CC (P = 0.0015) and CC-THV (P = 0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-ß(1-42) in neuronal cell culture. Immunohistopathological analysis of lens tissue obtained from two autopsy-confirmed AD subjects and two non-AD controls revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in delta catenin may underlie both cortical lens opacities in mid-life and subsequent MRI and cognitive changes that presage the development of AD.

Identification of novel NPRAP/δ-catenin-interacting proteins and the direct association of NPRAP with dynamin 2.

Neural plakophilin-related armadillo protein (NPRAP or δ-catenin) is a neuronal-specific protein that is best known for its interaction with presenilin 1 (PS1). Interestingly, the hemizygous loss of NPRAP is associated with severe mental retardation in cri du chat syndrome (CDCS), and mutations in PS1 cause an aggressive, early-onset form of Alzheimer's disease. Until recently, studies on the function of NPRAP have focused on its ability to modulate dendritic protrusion elaboration through its binding to cell adhesion and scaffolding molecules. However, mounting evidence indicates that NPRAP participates in intracellular signaling and exists in the nucleus, where it modulates gene expression. This apparent bifunctional nature suggests an elaborate neuronal role, but how NPRAP came to participate in such distinct subcellular events remains a mystery. To gain insight into this pathway, we immunoprecipitated NPRAP from human SH SY5Y cells and identified several novel interacting proteins by mass spectrometry. These included neurofilament alpha-internexin, interferon regulatory protein 2 binding factors, and dynamins 1 and 2. We further validated dynamin 2/NPRAP colocalization and direct interaction in vivo, confirming their bona fide partnership. Interestingly, dynamin 2 has established roles in endocytosis and actin assembly, and both of these processes have the potential to interface with the cell adhesion and intracellular signaling processes that involve NPRAP. Our data provide new avenues for approaching NPRAP biology and suggest a broader role for this protein than previously thought.

A nuclear function for the presenilin 1 neuronal partner NPRAP/δ-catenin.

Presenilin-1 (PS1) is a broadly expressed transmembrane protein that is often mutated in familial Alzheimer's disease (AD). In addition to its role in amyloid production, PS1 interacts with several protein partners, including the neural plakophilin-related armadillo protein (NPRAP or δ-catenin). Although studies have suggested that NPRAP affects cell adhesion, other data suggest that it can modulate gene expression. To investigate the transcriptional effects of NPRAP, we over-expressed NPRAP and measured gene expression using a microarray. We found that multiple genes, including BCHE, which has been linked to AD, were regulated by NPRAP. Furthermore, we showed that NPRAP nuclear translocation was required for gene regulation. Our results implicate NPRAP as a brain-specific signaling molecule with distinct roles at the cell junction and the nucleus.