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1.
Elife ; 102021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570495

RESUMO

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from fifteen whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.

2.
J Am Chem Soc ; 143(6): 2500-2508, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33529004

RESUMO

Electrostatic forces are important for protein folding and are favored targets of protein engineering. However, interactions between charged residues are difficult to study because of the complex network of interactions found in most proteins. We have designed a purposely simple system to investigate this problem by systematically introducing individual and pairs of charged and titratable residues in a protein otherwise free of such residues. We used constant pH molecular dynamics simulations, NMR spectroscopy, and thermodynamic double mutant cycles to probe the structure and energetics of the interaction between the charged residues. We found that the partial burial of surface charges contributes to a shift in pKa value, causing an aspartate to titrate in the neutral pH range. Additionally, the interaction between pairs of residues was found to be highly context dependent, with some pairs having no apparent preferential interaction, while other pairs would engage in coupled titration forming a highly stabilized salt bridge. We find good agreement between experiments and simulations and use the simulations to rationalize our observations and to provide a detailed mechanistic understanding of the electrostatic interactions.

3.
Sci Rep ; 11(1): 2010, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479373

RESUMO

The cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.

4.
PLoS One ; 16(1): e0244873, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33400700

RESUMO

BACKGROUND: Multiple studies have highlighted the negative impact of COVID-19 and its particular effects on vulnerable sub-populations. Complementing this work, here, we report on the social patterning of self-reported positive changes experienced during COVID-19 national lockdown in Scotland. METHODS: The CATALYST study collected data from 3342 adults in Scotland during weeks 9-12 of a national lockdown. Using a cross-sectional design, participants completed an online questionnaire providing data on key sociodemographic and health variables, and completed a measure of positive change. The positive change measure spanned diverse domains (e.g., more quality time with family, developing new hobbies, more physical activity, and better quality of sleep). We used univariate analysis and stepwise regression to examine the contribution of a range of sociodemographic factors (e.g., age, gender, ethnicity, educational attainment, and employment status) in explaining positive change. RESULTS: There were clear sociodemographic differences across positive change scores. Those reporting higher levels of positive change were female, from younger age groups, married or living with their partner, employed, and in better health. CONCLUSION: Overall our results highlight the social patterning of positive changes during lockdown in Scotland. These findings begin to illuminate the complexity of the unanticipated effects of national lockdown and will be used to support future intervention development work sharing lessons learned from lockdown to increase positive health change amongst those who may benefit.


Assuntos
/psicologia , Quarentena/psicologia , Isolamento Social/psicologia , Adulto , Ansiedade/epidemiologia , Ansiedade/prevenção & controle , /prevenção & controle , Controle de Doenças Transmissíveis/métodos , Estudos Transversais , Exercício Físico/psicologia , Família/psicologia , Feminino , Humanos , Masculino , Escócia/epidemiologia , Sono/fisiologia , Higiene do Sono , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologia , Inquéritos e Questionários
5.
Pediatr Pulmonol ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33470556

RESUMO

Cystic fibrosis (CF) patients utilize an average of 10 (±5) medications per day. Given the complexity of the medication regimen, the CF Foundation (CFF) recommends pharmacists as members of the CF care team. The areas of pharmacy services have been identified in the literature. "Limited access pharmacists" are consulted to answer questions, assist in evaluating serum drug concentrations, provide medication education, and monitor for drug-drug interactions. Reduction in hospital length of stay has been shown through this collaboration. "Full access pharmacists" provide comprehensive medication therapy management resulting in medication adherence and access improvements, sustainability of treatments, improved provider communication, reduced medication errors and costs, expedited medication refill authorization, increased utilization of respiratory therapists, enhanced discussion of medications with CF team members, and reduction in the number of pharmacies utilized by patients to fill CF medications. An integrated CF pharmacy team are essential members of the multidisciplinary CF care team that have been shown to improve in CF medication access, increases in body weight and body mass index, reduction in prior authorization submission times, reduction in medication delivery times, expedited medication refill authorizations, increased collaboration with respiratory therapists, augmented discussion of medication with CF team members, and reduction in the number of pharmacies utilized by CF patients. There is a need to further evaluate the impact of outpatient CF pharmacy services due to the improvements in the care on patients and families affected by CF, and as the number of CFF-accredited care centers integrates CF pharmacy teams throughout the country increases.

6.
Ann Surg ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33443907

RESUMO

OBJECTIVE: The aim of this study was to evaluate which mesh type yields lower recurrence and complication rates after ventral hernia repair. SUMMARY BACKGROUND DATA: More than 400,000 ventral hernia repairs are performed annually in the United States. Although the most effective method for repairing ventral hernias involves using mesh, whether to use biologic mesh versus synthetic mesh is controversial. METHODS: Single-blind, randomized, controlled, pragmatic clinical trial conducted from March 2014 through October 2018; 165 patients enrolled with an average follow up of 26 months. Patients were randomized 1:1 to have their ventral hernias repaired using either a biologic (porcine) or synthetic (polypropylene) mesh. The primary study outcome measure was hernia recurrence at 2 years. RESULTS: A total of 165 patients (68 men), mean age 55 years, were included in the study with a mean follow-up of 26 months. An intention-to-treat analysis noted that hernias recurred in 25 patients (39.7%) assigned to biologic mesh and in 14 patients (21.9%) assigned to synthetic mesh (P = 0.035) at 2 years. Subgroup analysis identified an increased rate of hernia recurrence in the biologic versus the synthetic mesh group under contaminated wound conditions (50.0% vs 5.9%; P for interaction = 0.041). Postoperative complication rates were similar for the 2 mesh types. CONCLUSIONS: The risk of hernia recurrence was significantly higher for patients undergoing ventral hernia repair with biologic mesh compared to synthetic mesh, with similar rates of postoperative complications. These data indicate that the use of synthetic mesh over biologic mesh to repair ventral hernias is effective and can be endorsed, including under contaminated wound conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02041494.

7.
Clin Otolaryngol ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33404189

RESUMO

BACKGROUND: Current UK referral criteria stipulate that hoarseness should be persistent to merit 2 week wait (2WW) or urgent suspicion of cancer (USOC) referral. This study delineates patterns of hoarseness presentation with a view to assisting referral pathways, and whereby reassurance could be provided. METHODS: A pre-existing database of patients referred with hoarseness under the urgent suspicion of cancer (USOC) category was analysed. Univariate and multivariate analyses were performed on a variety of demographic and comorbid features to produce odds ratios (OR) of features either related or not related to laryngeal cancer. RESULTS: Of 698 consecutive hoarseness referrals were studied. In these referrals there were 506(73%) with persistent hoarseness and 192(27%) with intermittent hoarseness. The most significant patient variables related to laryngeal cancer were persistent hoarseness (OR 4.97), recreational drug use (OR 4.94), male gender (OR 4.01) and weight loss (OR 3.75). Significant patient variables present not related to laryngeal cancer diagnosis were intermittent hoarseness (OR 0.2), the presence of cough (OR 0.2), globus sensation (OR 0.25) and recent viral infection (OR 0.29). CONCLUSION: The strongest association with cancer is seen in patients that are persistently hoarse. Patients with fluctuating hoarseness do not need an "urgent suspicion of cancer" referral. Additional demographic referral information could help to streamline the referral of these patients, and reassure others.

8.
Nano Lett ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33492966

RESUMO

The control of domain walls is central to nearly all magnetic technologies, particularly for information storage and spintronics. Creative attempts to increase storage density need to overcome volatility due to thermal fluctuations of nanoscopic domains and heating limitations. Topological defects, such as solitons, skyrmions, and merons, may be much less susceptible to fluctuations, owing to topological constraints, while also being controllable with low current densities. Here, we present the first evidence for soliton/soliton and soliton/antisoliton domain walls in the hexagonal chiral magnet Mn1/3NbS2 that respond asymmetrically to magnetic fields and exhibit pair-annihilation. This is important because it suggests the possibility of controlling the occurrence of soliton pairs and the use of small fields or small currents to control nanoscopic magnetic domains. Specifically, our data suggest that either soliton/soliton or soliton/antisoliton pairs can be stabilized by tuning the balance between intrinsic exchange interactions and long-range magnetostatics in restricted geometries.

9.
Chem Commun (Camb) ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33410438

RESUMO

The photochemical [2+2] cycloaddition of 3,5-bis-(2-(pyridin-4-yl)vinyl)pyridine (bpvp) in the flexible Cd-based metal-alkene frameworks produced different isomeric photoproducts depending on the auxiliary and guest molecules. The bulkiness of the guest molecules influenced the conformation of the ligand, and thus the outcome of the cycloaddition reaction.

10.
Crit Care Clin ; 37(1): 205-219, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33190771

RESUMO

The importance of evaluating and adjusting the nutritional state of critically ill patients has become a core principle of care. This article focuses on tools for the nutritional assessment of geriatric intensive care unit patients, including a review of imaging and other standardized techniques for evaluation of muscle mass, an indicator of malnutrition and sarcopenia. It concludes with a discussion of the interplay of malnutrition, reduced muscle mass/sarcopenia, and frailty. The goal of this multidimensional assessment is to identify those at risk and thereby initiate interventions to improve outcomes.

11.
Stem Cells ; 39(3): 331-344, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33326654

RESUMO

Irreversible denervation atrophy remains an unsolved clinical problem, and the role of skeletal muscle stem cell (MuSC, satellite cell) depletion in this process is unclear. We investigated the ability of MuSCs to regenerate muscle in the context of denervation. Three to 12 months following sciatic denervation in mice, MuSC number, size, EdU uptake, rate of division, and mitochondrial activity were increased. Following acute myotoxin injury, denervated muscles formed new muscle fibers in situ. MuSCs isolated via flow cytometry from denervated mouse muscle, or from atrophic denervated gluteus maximus muscles of humans with complete spinal cord injuries two decades prior, formed new muscle fibers and reoccupied the anatomic niche after transplantation into uninjured muscle. Our results show unequivocally that, even after prolonged denervation, MuSCs retain intrinsic regenerative potential similar to that of uninjured MuSCs. Treatment of denervation atrophy will require elucidating the non-MuSC environmental changes in muscle that prevent functional regeneration.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33259180

RESUMO

High-efficiency silicon solar cells rely on some form of passivating contact structure to reduce recombination losses at the crystalline silicon surface and losses at the metal/Si contact interface. One such structure is polycrystalline silicon (poly-Si) on oxide, where heavily doped poly-Si is deposited on a SiOx layer grown directly on the crystalline silicon (c-Si) wafer. Depending on the thickness of the SiOx layer, the charge carriers can cross this layer by tunneling (<2 nm SiOx thickness) or by direct conduction through disruptions in the SiOx, often referred to as pinholes, in thicker SiOx layers (>2 nm). In this work, we study structures with tunneling- or pinhole-like SiOx contacts grown on pyramidally textured c-Si wafers and expose variations in the SiOx layer properties related to surface morphology using electron-beam-induced current (EBIC) imaging. Using EBIC, we identify and mark regions with potential pinholes in the SiOx layer. We further perform high-resolution transmission electron microscopy on the same areas, thus allowing us to directly correlate locally enhanced carrier collection with variations in the structure of the SiOx layer. Our results show that the pinholes in the SiOx layer preferentially form in different locations based on the annealing conditions used to form the device. With greater understanding of these processes and by controlling the surface texture geometry, there is potential to control the size and spatial distribution of oxide disruptions in silicon solar cells with poly-Si on oxide-type contacts; usually, this is a random phenomenon on polished or planar surfaces. Such control will enable us to consistently produce high-efficiency devices with low recombination currents and low junction resistances using this contact structure.

13.
Sci Rep ; 10(1): 21923, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318505

RESUMO

MicroRNAs have been shown to play a role in cartilage development, homeostasis and breakdown during osteoarthritis. We previously identified miR-3085 in humans as a chondrocyte-selective microRNA, however it could not be detected by Northern blot. The aim of the current study was to prove that miR-3085 is a microRNA and to investigate the function of miR-3085 in signaling pathways relevant to cartilage homeostasis and osteoarthritis. Here, we confirm that miR-3085 is a microRNA and not another class of small RNA using (1) a pre-miR hairpin maturation assay, (2) expression levels in a Dicer null cell line, and (3) Ago2 pulldown. MicroRNA-3085-3p is expressed more highly in micromass than monolayer cultured chondrocytes. Transfection of miR-3085-3p into chondrocytes decreases expression of COL2A1 and ACAN, both of which are validated as direct targets of miR-3085-3p. Interleukin-1 induces the expression of miR-3085-3p, at least in part via NFκB. In a feed-forward mechanism, miR-3085-3p then potentiates NFκB signaling. However, at early time points after transfection, its action appears to be inhibitory. MyD88 has been shown to be a direct target of miR-3085-3p and may be responsible for the early inhibition of NFκB signaling. However, at later time points, MyD88 knockdown remains inhibitory and so other functions of miR-3085-3p are clearly dominant. TGFß1 also induces the expression of miR-3085-3p, but in this instance, it exerts a feedback inhibition on signaling with SMAD3 and SMAD4 shown to be direct targets. This in vitro analysis shows that miR-3085-3p functions in chondrocytes to induce IL-1-signaling, reduce TGFß1 signaling, and inhibit expression of matrix genes. These data suggest that miR-3085-3p has a role in chondrocyte function and could contribute to the process of osteoarthritis.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33327556

RESUMO

We examine the impact of the COVID-19 outbreak and concomitant restrictions (i.e., lockdown) on 24-hour movement behaviors (i.e., physical activity, sitting, sleep) in a purposive sample of people (n = 3230) reporting change recruited online. Participants' self-reported time spent in moderate-to-vigorous physical activity (MVPA), walking, sitting and sleep prior to lockdown (T1), during the first national lockdown (T2) and as restrictions initially started to ease (T3). For each 24-hour movement behavior, category-shifts are reported (positive, negative or did not change), as well as the percentage of participants recording positive/negative changes across clusters of behaviors and the percentage of participants recording improvement or maintenance of change across time. From T1 to T2 walking decreased, whereas MVPA, sitting and sleep increased, from T2 to T3 levels returned to pre-lockdown for all but MVPA. Participants who changed one behavior positively were more likely to report a positive change in another and 50% of those who reported positive changes from T1 to T2 maintained or improved further when restrictions started to ease. The current study showed that a large proportion of the sample reported positive changes, most notably those displaying initially poor levels of each behavior. These findings will inform salutogenic intervention development.


Assuntos
Exercício Físico , Pandemias , Comportamento Sedentário , Sono , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escócia , Postura Sentada , Adulto Jovem
17.
Front Hum Neurosci ; 14: 581026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250730

RESUMO

Gait is one of the fundamental behaviors we use to interact with the world. The functionality of the locomotor system is thus related to enriching interactions with our environment. The posterior parietal cortex (PPC) has been found to contribute to motor adaptation during both visuomotor and postural adaptation tasks. Additionally, structural or functional deficits of the PPC lead to impairments in gaits such as shortened steps and increased step width. Based on the aforementioned roles of the PPC, and the importance of gait adaptability, the current investigation sought to identify the role of the PPC in gait adaptation. To achieve this, we performed transcranial direct current stimulation (tDCS) over the bilateral PPC before performing a split-belt treadmill gait adaptation paradigm. We used three stimulation conditions in a within-subject design. tDCS was administered in a randomized and double-blinded order. Following each stimulation session, subjects first performed baseline walking with both belts running at the same speed. Then, subjects walked for 15 min on an uncoupled treadmill, with the belts being driven at a 3:1 speed ratio. Last, they returned to normal (i.e., tied-belt) walking for 5 min. Results from 15 young and healthy subjects identified that subjects required more steps to adapt to split-belt walking following the suppression of the left hemisphere PPC, contralateral to the fast belt. Furthermore, while suppression of the left hemisphere PPC did not increase the number of steps required to re-adapt to tied-belt walking, this condition did lead to increased magnitude of after-effects. Together, these findings indicate that the PPC is involved in locomotor adaptation. These results support previous literature regarding the upper body or postural adaptation and extend these findings to the realm of gait. Results highlight the PPC as a potential target for neurorehabilitation designed to improve gait adaptability.

18.
J Physiol ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052608

RESUMO

KEY POINTS: microRNAs (miRs) are small non-coding molecules that regulate post-transcriptional target gene expression. miRs are involved in regulating cellular activities in response to mechanical loading in all physiological systems, although it is largely unknown whether this response differs with increasing magnitudes of load. miR-221, miR-222, miR-21-5p and miR-27a-5p were significantly increased in ex vivo cartilage explants subjected to increasing load magnitude and in in vivo joint cartilage exposed to abnormal loading. TIMP3 and CPEB3 are putative miR targets in chondrocytes Identification of mechanically regulated miRs that have potential to impact on tissue homeostasis provides a mechanism by which load-induced tissue behaviour is regulated, in both health and pathology, in all physiological systems. ABSTRACT: MicroRNAs (miRs) are small non-coding molecules that regulate post-transcriptional target gene expression and are involved in mechano-regulation of cellular activities in all physiological systems. It is unknown whether such epigenetic mechanisms are regulated in response to increasing magnitudes of load. The present study investigated mechano-regulation of miRs in articular cartilage subjected to 'physiological' and 'non-physiological' compressive loads in vitro as a model system and validated findings in an in vivo model of abnormal joint loading. Bovine full-depth articular cartilage explants were loaded to 2.5 MPa (physiological) or 7 MPa (non-physiological) (1 Hz, 15 min) and mechanically-regulated miRs identified using next generation sequencing and verified using a quantitative PCR. Downstream targets were verified using miR-specific mimics or inhibitors in conjunction with 3'-UTR luciferase activity assays. A subset of miRs were mechanically-regulated in ex vivo cartilage explants and in vivo joint cartilage. miR-221, miR-222, miR-21-5p and miR-27a-5p were increased and miR-483 levels decreased with increasing load magnitude. Tissue inhibitor of metalloproteinase 3 (TIMP3) and cytoplasmic polyadenylation element binding protein 3 (CPEB3) were identified as putative downstream targets. Our data confirm miR-221 and -222 mechano-regulation and demonstrates novel mechano-regulation of miR-21-5p and miR-27a-5p in ex vivo and in vivo cartilage loading models. TIMP3 and CPEB3 are putative miR targets in chondrocytes. Identification of specific miRs that are regulated by increasing load magnitude, as well as their potential to impact on tissue homeostasis, has direct relevance to other mechano-sensitive physiological systems and provides a mechanism by which load-induced tissue behaviour is regulated, in both health and pathology.

19.
Dalton Trans ; 49(44): 15527-15547, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33107541

RESUMO

Ru-Catalyzed acceptorless dehydrogenative coupling (ADC) and auto-transfer-hydrogenative (ATH) reactions are effective, versatile transformations for the constructions of N-heteroaromatic compounds from alcohols. Water and hydrogen are the by-products and the starting alcohols are less toxic, more readily available and more easily handled than their halogenated counterparts. A variety of homogeneous ruthenium catalysts, alcohols and partner-substrates such as amines, ammonia, amidines and nitriles, have been used to build N-heteroaromatic compounds in one-pot, multi-step syntheses. This review details recently reported Ru catalysts employed for these reactions, describing the scope of each methodology, proposed reaction mechanisms, regioselectivity of coupling and applications in synthesis.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33086294

RESUMO

PURPOSE: To study practice patterns in European cataract surgery over a 10-year period. SETTING: European clinics affiliated to the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO). DESIGN: Registry cohort study. METHODS: The EUREQUO contains preoperative, intraoperative, and postoperative parameters reported by surgeons in many European clinics. All data reported to the registry are anonymized. Preoperative parameters included age, sex, visual acuity, target refraction, ocular comorbidity, and surgical difficulties. Surgical data included anaesthesia, surgical technique, intraocular lens optic biomaterial, and complications. Postoperative parameters included visual acuity, refraction, and short-term complications. RESULTS: During the study period (January 1. 2008-December 31, 2017) a total of 2,714,108 cataract extractions were reported to the EUREQUO. Preoperative data changed over time, with decreases in mean age (74.5 to 73.0), proportion of women from 60.6% (100,373/165,628) to 57.2% (174,908/305,845), and proportion of co-existing eye diseases from 30.0% (49,638/165,650) to 27.0% (82,704/305,846); and improvements in preoperative visual acuity (mean logMAR 0.46 to 0.37). The use of topical anaesthesia increased over time from 28.1% (26,238/93,320) to 71.7% (130,525/182,083). Surgical complications showed a significant decrease from 2.5% (4,107/165,650) to 1.2% (3,573/305,846). The visual outcome improved over time (mean logMAR 0.08 to 0.05), as did the absolute median prediction error (0.38 diopter [D] to 0.28 D). CONCLUSIONS: Trends in European cataract surgery practice patterns from 2008 to 2017 have moved toward younger patients with better preoperative visual acuity, fewer surgical complications, and better predicted refractions and visual outcomes.

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