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Abstract In several orthopedic procedures, the accurate use of surgical power tools is critical to avoid damage to surrounding tissues. As such, various guidance techniques and safety measures were developed. Augmented reality (AR) guidance shows promise but requires validation. We evaluated a new approach using an inside-out infrared tracking solution for the HoloLens to compensate for its limited tracking performance. Eighteen participants with varying levels of experience (student, trainee, expert) each drilled twelve trajectories (six perpendicular, six oblique) in equidimensional wooden logs. Three different techniques were evaluated: freehand drilling; proprioception-guided drilling towards the contralateral index finger; and AR-guided drilling using a tracked drill and a virtual overlay of the log with predefined guidance vectors. The angular errors between planned and performed trajectories were compared using a mixed-design ANOVA. The results demonstrated that guidance technique (p

Crystal structures for all enzyme states of leucyl-tRNA synthetase in Neisseria gonorrhoeae reveal multi-domain conformational changes that correlate with a local peptide-plane flip in the active site to compartmentalize catalytic steps.

In Finland, older persons are entitled to needs-tested public home care services. Home care mainly assists with personal care, activities of daily living and medical needs. It is complemented with auxiliary services that offer help with instrumental activities of daily living. In Finland, municipalities are responsible for organising public home care services. These services are mainly tax-funded, but user fees are also charged. In this article, we examine the levels of user fees of home care and auxiliary services in Finnish municipalities in 2018. The data analysis consists of descriptive statistics and exemplary cases of costs to the service users. The results show that user fees may represent a significant share of older persons' monthly incomes. Consequently, home care users, especially those with low incomes, are at risk of economic deprivation and non-take-up of the services. We also found substantial variation in user fees across municipalities, causing regional inequality. [ABSTRACT FROM AUTHOR]

Older adults face inequalities in care. The concept of care poverty has been developed to point out how unmet care needs are not just an individual issue but a phenomenon linked to social and economic disadvantage and societal inequality. In this paper, we approach the question of care poverty by focusing on its intertwinement with emotions and the home space. We analyze how the presence, or more commonly absence, of care shapes interviewees’ descriptions of emotional experiences tied to the home space. Our data consists of 12 semi-structured interviews conducted in 2019 and 2020 with customers of outreach work for older adults in Finland. These customers typically face a situation that can be characterized as care poverty: their care needs are not (or have not been) met by either the service system or informal sources. When analyzing the data, we followed the guidelines for thematic analysis proposed by Braun and Clarke. Our analysis shows how care and lack of care transform interviewees’ emotional connections with the home space, highlighting particularly three main themes: insecurity, isolation and belongingness. Our analysis reveals how lack of care can transform the home into an unsafe place; a space characterized by isolation, or a space where one sometimes ceases to feel at ease or “like oneself.” The emotional experience of home and being adequately cared for is also tied to the sense of (not) belonging to a place. Based on our analysis, we argue that as an experience, care poverty is not just about individual unmet needs and/or a scarcity of resources at the societal level; it should also be understood as deeply relational—born and shaped in interactions (or the lack of interactions) among people, and lived in and through relationships with others. Furthermore, we highlight the importance of a sense of belonging to the feeling of being adequately cared for.

Natural resistance-associated macrophage protein 2 (NRAMP 2; also known as DMT1 and encoded by SLC11A2) is mainly known for its iron transport activity. Recently, the DMT1 isoform lacking the iron-response element (non-IRE) was associated with aberrant NOTCH pathway activity. In this report, we investigated the function of DMT1 nonIRE in normal and malignant hematopoiesis. Knockdown of Dmt1 nonIRE in mice showed that it has non-canonical functions in hematopoietic stem cell differentiation: its knockdown suppressed development along the myeloid and lymphoid lineages, while promoting the production of platelets. These phenotypic effects on the hematopoietic system induced by Dmt1 nonIRE knockdown were linked to suppression of Notch/Myc pathway activity. Conversely, our data indicate a non-canonical function for DMT1 nonIRE overexpression in boosting NOTCH pathway activity in T-cell leukemia homeobox protein 1 (TLX1)-defective leukemia. This work sets the stage for future investigation using a multiple-hit T-cell acute lymphoblastic leukemia (T-ALL) model to further investigate the function of DMT1 nonIRE in T-ALL disease development and progression. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N1-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N9-position, we obtained the N3-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N7-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these “base-flipped” analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N3-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N1 and the N6-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis.

In further study of our series of six-membered ring-containing nucleic acids, different 1',3'-di-O-methyl altropyranoside nucleoside analogs (DMANA) were synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. Following assembly into oligonucleotides (ONs), their affinity for natural oligonucleotides was evaluated by thermal denaturation of the respective duplexes. Data were compared with results obtained previously for both anhydrohexitol (HNAs) and 3'-O-methylated altrohexitol modified ONs (MANAs). We hereby demonstrate that ONs modified with DMANA monomers, unlike some of our previously described analogues with constrained 6-membered hexitol rings, did not improve thermodynamic stability of dsRNA complexes, most probably in view of an energetic penalty when forced in the required 1C4 pairing conformation. Overall, a single incorporation was more or less tolerated or even positive for the adenine congener, but incorporation of a second modification afforded a slight destabilization (except for A), while a fully modified sequence displayed a thermal stability of −0.3 °C per modification. The selectivity of pairing remained very high, and the new modification upon incorporation into a DNA strand, strongly destabilized the corresponding DNA duplexes. Unfortunately, this new modification does not bring any advantage to be further evaluated for antisense or siRNA applications.

Emerging antibiotic resistance in pathogenic bacteria and reduction of compounds in the existing antibiotics discovery pipeline is the most critical concern for healthcare professionals. A potential solution aims to explore new or existing targets/compounds. Inhibition of bacterial aminoacyl-tRNA synthetase (aaRSs) could be one such target for the development of antibiotics. The aaRSs are a group of enzymes that catalyze the transfer of an amino acid to their cognate tRNA and therefore play a pivotal role in translation. Thus, selective inhibition of these enzymes could be detrimental to microbes. The 5′-O-(N-(L-aminoacyl)) sulfamoyladenosines (aaSAs) are potent inhibitors of the respective aaRSs, however due to their polarity and charged nature they cannot cross the bacterial membranes. In this work, we increased the lipophilicity of these existing aaSAs in an effort to promote their penetration through the bacterial membrane. Two strategies were followed, either attaching a (permanent) alkyl moiety at the adenine ring via alkylation of the N6-position or introducing a lipophilic biodegradable prodrug moiety at the alpha-terminal amine, totaling eight new aaSA analogues. All synthesized compounds were evaluated in vitro using either a purified Escherichia coli aaRS enzyme or in presence of total cellular extract obtained from E. coli. The prodrugs showed comparable inhibitory activity to the parent aaSA analogues, indicating metabolic activation in cellular extracts, but had little effect on bacteria. During evaluation of the N6-alkylated compounds against different microbes, the N6-octyl containing congener 6b showed minimum inhibitory concentration (MIC) of 12.5 µM against Sarcina lutea while the dodecyl analogue 6c displayed MIC of 6.25 µM against Candida albicans.