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1.
Eur Heart J Imaging Methods Pract ; 2(1): qyae047, 2024 Jan.
Article En | MEDLINE | ID: mdl-38845796

Aims: We aimed to identify the distinctive cardiovascular magnetic resonance (CMR) features of patients with left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF) of presumed non-ischaemic aetiology. The secondary aim was to determine whether these individuals exhibit characteristics that could potentially serve as predictors of left ventricular ejection fraction (LVEF) recovery as compared with patients without LBBB. Methods and results: We prospectively recruited patients with HFrEF (LVEF ≤ 40%) on echocardiography who were referred for early CMR examination. Patients with an established diagnosis of coronary artery disease and known structural or congenital heart disease were excluded. LV recovery was defined as achieving ≥10% absolute improvement to ≥40% in LVEF between baseline evaluation to CMR. A total of 391 patients were recruited including 115 (29.4%) with LBBB. Compared with HF patients without LBBB, those with LBBB exhibited larger left ventricles and smaller right ventricles, but no differences were observed with respect to LVEF (35.8 ± 12 vs. 38 ± 12%, P = 0.105). The overall rate of LV recovery from baseline echocardiogram to CMR (70 [42-128] days) was not significantly different between LBBB and non-LBBB patients (27.8% vs. 31.5%, P = 0.47). Reduced LVEF remained an independent predictor of LV non-recovery only in patients with LBBB. Conclusion: Patients presenting with HFrEF and LBBB had larger LV cavities and smaller RV cavities than those without LBBB but no difference in prevalence of scar or ischaemia. The rates of LV recovery were similar between both groups, which supports current guidelines to defer device therapy until 3-6 months of guideline-directed medical therapy, rather than early CMR and device implantation.

2.
Acta Crystallogr D Struct Biol ; 80(Pt 4): 259-269, 2024 Apr 01.
Article En | MEDLINE | ID: mdl-38573522

The widespread adoption of cryoEM technologies for structural biology has pushed the discipline to new frontiers. A significant worldwide effort has refined the single-particle analysis (SPA) workflow into a reasonably standardized procedure. Significant investments of development time have been made, particularly in sample preparation, microscope data-collection efficiency, pipeline analyses and data archiving. The widespread adoption of specific commercial microscopes, software for controlling them and best practices developed at facilities worldwide has also begun to establish a degree of standardization to data structures coming from the SPA workflow. There is opportunity to capitalize on this moment in the maturation of the field, to capture metadata from SPA experiments and correlate the metadata with experimental outcomes, which is presented here in a set of programs called EMinsight. This tool aims to prototype the framework and types of analyses that could lead to new insights into optimal microscope configurations as well as to define methods for metadata capture to assist with the archiving of cryoEM SPA data. It is also envisaged that this tool will be useful to microscope operators and facilities looking to rapidly generate reports on SPA data-collection and screening sessions.


Single Molecule Imaging , Software , Cryoelectron Microscopy , Data Collection , Specimen Handling
3.
Nat Commun ; 15(1): 2908, 2024 Apr 04.
Article En | MEDLINE | ID: mdl-38575616

Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.


Alzheimer Disease , Cognitive Dysfunction , Humans , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Brain/metabolism , Biomarkers/cerebrospinal fluid , Atrophy
4.
Nat Hum Behav ; 8(5): 846-877, 2024 May.
Article En | MEDLINE | ID: mdl-38438653

Music is present in every known society but varies from place to place. What, if anything, is universal to music cognition? We measured a signature of mental representations of rhythm in 39 participant groups in 15 countries, spanning urban societies and Indigenous populations. Listeners reproduced random 'seed' rhythms; their reproductions were fed back as the stimulus (as in the game of 'telephone'), such that their biases (the prior) could be estimated from the distribution of reproductions. Every tested group showed a sparse prior with peaks at integer-ratio rhythms. However, the importance of different integer ratios varied across groups, often reflecting local musical practices. Our results suggest a common feature of music cognition: discrete rhythm 'categories' at small-integer ratios. These discrete representations plausibly stabilize musical systems in the face of cultural transmission but interact with culture-specific traditions to yield the diversity that is evident when mental representations are probed across many cultures.


Auditory Perception , Cross-Cultural Comparison , Music , Music/psychology , Humans , Male , Adult , Female , Auditory Perception/physiology , Young Adult , Cognition/physiology
5.
J Periodontol ; 2024 Mar 13.
Article En | MEDLINE | ID: mdl-38476115

BACKGROUND: The aim of the present study was to evaluate the subgingival microbiome in patients with grade C molar-incisor pattern periodontitis (C-MIP) affecting the primary or permanent dentitions. METHODS: DNA was isolated from subgingival biofilm samples from diseased and healthy sites from 45 C-MIP patients and subjected to phylogenetic microarray analysis. C-MIP sites were compared between children affected in the primary to those affected in the permanent dentitions. Within-subject differences between C-MIP-affected sites and dentition-matched healthy sites were also evaluated. RESULTS: C-MIP sites of subjects affected in the primary dentition showed partially overlapping but distinct microbial communities from C-MIP permanent dentition sites (p < 0.05). Differences were due to increased levels in primary C-MIP sites of certain species of the genera Capnocytophaga and Leptotrichia, while C-MIP permanent dentition sites showed higher prevalence of Filifactor alocis. Aggregatibacter actinomycetemcomitans (Aa) was among species seen in high prevalence and levels in both primary and permanent C-MIP sites. Moreover, both permanent and primary C-MIP sites showed distinct microbial communities when compared to dentition-matched healthy sites in the same subject (p < 0.01). CONCLUSIONS: Primary and permanent teeth with C-MIP showed a dysbiotic microbiome, with children affected in the primary dentition showing a distinct profile from those affected in the permanent dentition. However, Aa was enriched in both primary and permanent diseased sites, confirming that this microorganism is implicated in C-MIP in both dentitions.

6.
Nat Commun ; 15(1): 2615, 2024 Mar 23.
Article En | MEDLINE | ID: mdl-38521766

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.


Alzheimer Disease , Humans , Alzheimer Disease/diagnosis , Neuropathology , Plasma , Neurofibrillary Tangles , Autopsy , tau Proteins , Biomarkers , Amyloid beta-Peptides
7.
Clin Exp Dent Res ; 10(1): e833, 2024 02.
Article En | MEDLINE | ID: mdl-38345521

OBJECTIVES: In this study, the aim was to investigate the medium- to long-term impact of peri-implantitis treatment upon clinical parameters and implant stability quotient values and to ascertain if magnetic resonance frequency analysis can be used as a diagnostic tool to demonstrate postoperative healing following treatment of peri-implantitis. MATERIALS AND METHODS: A total of n = 26 patients (n = 86 implants) diagnosed with peri-implantitis were recruited for this prospective cohort study and four different treatment modalities were used. Baseline measurements of a number of clinical parameters as well as implant stability measurements in the form of ISQ were recorded. These measurements were repeated at 6, 12, and 24-36 months following treatment. Analysis of variance was performed for all implants treated as well as separately for each treatment modality. A regression model was also used to determine factors affecting ISQ measurements over time. RESULTS: Treatment of peri-implantitis resulted in significant improvements of both average PPDs and BOP (p < .0001 and p < .01). ISQ values marginally improved initially for all treatment modalities, but improvement was only maintained for 2-3 years in treatment modalities I (+1.28), III (+1.49), and IV (+2.92). There was a statistically significant negative linear correlation between average PPD and the ISQ values recorded both at baseline (r = -.618, p < 0.0001) and at 2/3 years (r = -.604, p < 0.0001). CONCLUSION: Over the 2-3-year follow-up period, all four treatment modalities led to improved clinical and radiographic peri-implant parameters but implant stability posttreatment, as indicated by the fact that the recorded ISQ scores remained stable. As a result, use of MRFA as an adjunct to the traditionally used periodontal and radiographic tools for the evaluation of postoperative implant stability following the treatment of peri-implant disease cannot be recommended.


Dental Implants , Peri-Implantitis , Humans , Peri-Implantitis/diagnosis , Peri-Implantitis/surgery , Dental Implants/adverse effects , Follow-Up Studies , Prospective Studies
8.
Microb Genom ; 10(2)2024 Feb.
Article En | MEDLINE | ID: mdl-38358325

The COVID-19 pandemic has seen large-scale pathogen genomic sequencing efforts, becoming part of the toolbox for surveillance and epidemic research. This resulted in an unprecedented level of data sharing to open repositories, which has actively supported the identification of SARS-CoV-2 structure, molecular interactions, mutations and variants, and facilitated vaccine development and drug reuse studies and design. The European COVID-19 Data Platform was launched to support this data sharing, and has resulted in the deposition of several million SARS-CoV-2 raw reads. In this paper we describe (1) open data sharing, (2) tools for submission, analysis, visualisation and data claiming (e.g. ORCiD), (3) the systematic analysis of these datasets, at scale via the SARS-CoV-2 Data Hubs as well as (4) lessons learnt. This paper describes a component of the Platform, the SARS-CoV-2 Data Hubs, which enable the extension and set up of infrastructure that we intend to use more widely in the future for pathogen surveillance and pandemic preparedness.


COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Pandemics , COVID-19/epidemiology , Genomics , Information Dissemination
9.
Nat Commun ; 15(1): 1482, 2024 Feb 19.
Article En | MEDLINE | ID: mdl-38369535

The phenomenon of musical consonance is an essential feature in diverse musical styles. The traditional belief, supported by centuries of Western music theory and psychological studies, is that consonance derives from simple (harmonic) frequency ratios between tones and is insensitive to timbre. Here we show through five large-scale behavioral studies, comprising 235,440 human judgments from US and South Korean populations, that harmonic consonance preferences can be reshaped by timbral manipulations, even as far as to induce preferences for inharmonic intervals. We show how such effects may suggest perceptual origins for diverse scale systems ranging from the gamelan's slendro scale to the tuning of Western mean-tone and equal-tempered scales. Through computational modeling we show that these timbral manipulations dissociate competing psychoacoustic mechanisms underlying consonance, and we derive an updated computational model combining liking of harmonicity, disliking of fast beats (roughness), and liking of slow beats. Altogether, this work showcases how large-scale behavioral experiments can inform classical questions in auditory perception.


Music , Humans , Psychoacoustics , Music/psychology , Auditory Perception , Emotions , Judgment , Acoustic Stimulation
10.
Ecol Lett ; 27(1): e14348, 2024 Jan.
Article En | MEDLINE | ID: mdl-38288869

Sourcing seed from local populations has been the long-standing default for native restoration plantings for numerous eco-evolutionary reasons. However, rapidly changing environments are revealing risks associated with both non-local and local provenancing. As alternative strategies gain interest, we argue to progress seed sourcing discussions towards developing risk-based decision-making that weighs the risks of changing and not changing in a changing environment, transcending historic default positions and local versus non-local debates.


Biological Evolution , Seeds
11.
Cell Rep ; 43(2): 113717, 2024 Feb 27.
Article En | MEDLINE | ID: mdl-38285738

The homeostatic regulation of serine palmitoyltransferase (SPT) activity in yeast involves N-terminal phosphorylation of Orm proteins, while higher eukaryotes lack these phosphorylation sites. Although recent studies have indicated a conserved ceramide-mediated feedback inhibition of the SPT-ORM/ORMDL complex in higher eukaryotes, its conservation and relationship with phosphorylation regulation in yeast remain unclear. Here, we determine the structure of the yeast SPT-Orm2 complex in a dephosphomimetic state and identify an evolutionarily conserved ceramide-sensing site. Ceramide stabilizes the dephosphomimetic Orm2 in an inhibitory conformation, facilitated by an intramolecular ß-sheet between the N- and C-terminal segments of Orm2. Moreover, we find that a phosphomimetic mutant of Orm2, positioned adjacent to its intramolecular ß-sheet, destabilizes the inhibitory conformation of Orm2. Taken together, our findings suggest that both Orm dephosphorylation and ceramide binding are crucial for suppressing SPT activity in yeast. This highlights a distinctive regulatory mechanism in yeast involving the collaborative actions of phosphorylation and ceramide.


Ceramides , Saccharomyces cerevisiae Proteins , Ceramides/metabolism , Saccharomyces cerevisiae/metabolism , Sphingolipids/metabolism , Phosphorylation , Proteins/metabolism , Serine C-Palmitoyltransferase/genetics , Serine C-Palmitoyltransferase/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism
12.
Alzheimers Dement ; 20(2): 1239-1249, 2024 Feb.
Article En | MEDLINE | ID: mdl-37975513

INTRODUCTION: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited. METHODS: We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaßeta Brain Research Center's Alzheimer's At-Risk Cohort [ß-AARC]). RESULTS: UGOT p-tau217 showed high accuracy (area under the curve [AUC] = 0.80-0.91) identifying amyloid beta (Aß) pathology, determined either by Aß positron emission tomography or CSF Aß42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aß42/40 ratio (AUC = 0.91). DISCUSSION: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.


Alzheimer Disease , Cognitive Dysfunction , Humans , Amyloid beta-Peptides/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Positron-Emission Tomography , Brain , Biomarkers/cerebrospinal fluid
13.
Nucleic Acids Res ; 52(D1): D891-D899, 2024 Jan 05.
Article En | MEDLINE | ID: mdl-37953337

Ensembl (https://www.ensembl.org) is a freely available genomic resource that has produced high-quality annotations, tools, and services for vertebrates and model organisms for more than two decades. In recent years, there has been a dramatic shift in the genomic landscape, with a large increase in the number and phylogenetic breadth of high-quality reference genomes, alongside major advances in the pan-genome representations of higher species. In order to support these efforts and accelerate downstream research, Ensembl continues to focus on scaling for the rapid annotation of new genome assemblies, developing new methods for comparative analysis, and expanding the depth and quality of our genome annotations. This year we have continued our expansion to support global biodiversity research, doubling the number of annotated genomes we support on our Rapid Release site to over 1700, driven by our close collaboration with biodiversity projects such as Darwin Tree of Life. We have also strengthened support for key agricultural species, including the first regulatory builds for farmed animals, and have updated key tools and resources that support the global scientific community, notably the Ensembl Variant Effect Predictor. Ensembl data, software, and tools are freely available.


Databases, Genetic , Genomics , Animals , Genome , Molecular Sequence Annotation , Phylogeny , Software , Humans
14.
Alzheimers Dement ; 20(1): 745-751, 2024 Jan.
Article En | MEDLINE | ID: mdl-37858957

INTRODUCTION: Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. METHODS: We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). RESULTS: Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001). DISCUSSION: Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.


Alzheimer Disease , Creutzfeldt-Jakob Syndrome , Humans , Alzheimer Disease/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Brain , Biomarkers/cerebrospinal fluid , Diagnosis, Differential , Amyloid beta-Peptides/cerebrospinal fluid
15.
Philos Trans R Soc Lond B Biol Sci ; 379(1895): 20220420, 2024 Jan 29.
Article En | MEDLINE | ID: mdl-38104601

Expectation is crucial for our enjoyment of music, yet the underlying generative mechanisms remain unclear. While sensory models derive predictions based on local acoustic information in the auditory signal, cognitive models assume abstract knowledge of music structure acquired over the long term. To evaluate these two contrasting mechanisms, we compared simulations from four computational models of musical expectancy against subjective expectancy and pleasantness ratings of over 1000 chords sampled from 739 US Billboard pop songs. Bayesian model comparison revealed that listeners' expectancy and pleasantness ratings were predicted by the independent, non-overlapping, contributions of cognitive and sensory expectations. Furthermore, cognitive expectations explained over twice the variance in listeners' perceived surprise compared to sensory expectations, suggesting a larger relative importance of long-term representations of music structure over short-term sensory-acoustic information in musical expectancy. Our results thus emphasize the distinct, albeit complementary, roles of cognitive and sensory expectations in shaping musical pleasure, and suggest that this expectancy-driven mechanism depends on musical information represented at different levels of abstraction along the neural hierarchy. This article is part of the theme issue 'Art, aesthetics and predictive processing: theoretical and empirical perspectives'.


Music , Pleasure , Auditory Perception , Music/psychology , Motivation , Bayes Theorem , Cognition , Acoustic Stimulation/methods
16.
J Strength Cond Res ; 38(1): 1-9, 2024 Jan 01.
Article En | MEDLINE | ID: mdl-38085618

ABSTRACT: Harrison, PW, James, LP, Jenkins, DG, McGuigan, MR, Holmberg, PM, and Kelly, VG. The effects of low-load squat jump and maximal isometric priming exercise on muscular performance and perceptual state. J Strength Cond Res 38(1): 1-9, 2024-The aim of this study was to examine responses at 3 and 27 hours after low-load jump squat (LL) and maximal isometric half-squat (ISO) priming stimuli. Fifteen resistance-trained males performed LL (4 × 3 at 20% 1 repetition maximum [1RM]), ISO (4 × 3 seconds), and control (CON) activities (standardized warm-up) in a randomized and counterbalanced order. Countermovement jump (CMJ) and isometric midthigh pull tests were conducted to assess performance changes after priming and CON activities. No clear changes in CMJ measures were found after priming activities compared with CON. However, small effect size improvements were found after priming stimuli completed on the same day. A 2.9% decrease in concentric phase duration (CI = 0.3-5.9, p = 0.333, Cliff's delta = -0.156) and a 9.1% increase in RSImod (CI = 0.2-12.3, p = 0.151, Cliff's delta = -0.218) occurred at 3 hours after LL compared with CON. Braking phase duration (CI = 0.8-10.6, p = 0.333, Cliff's delta = -0.213) was 2.9% shorter at 3 hours after ISO compared with CON. No clear changes in isometric peak force occurred after priming activities compared with CON. Additionally, questionnaires were completed to assess perceptual state and perceived effectiveness of the priming stimulus to influence performance. An increase in the "effect of activity" was perceived at 3 hours after LL and ISO (p = 0.013-0.044, Cliff's delta = 0.578-0.6) and at 27 hours after ISO (p = 0.99, Cliff's delta = 0.173) compared with CON. An increase in "muscular heaviness" was also reported at 3 hours after ISO compared with CON (p = 0.199, Cliff's delta = 0.320). The collective findings suggest limited benefits over the day after LL and ISO priming stimuli. However, as there was substantial variation in individual responses, the relative nature of priming responses should be considered when prescribing similar strategies in practical environments.


Athletic Performance , Resistance Training , Warm-Up Exercise , Humans , Male , Athletic Performance/physiology , Exercise/physiology , Muscle Strength/physiology , Posture
17.
J Strength Cond Res ; 38(1): 174-179, 2024 Jan 01.
Article En | MEDLINE | ID: mdl-38085626

ABSTRACT: Harrison, PW, James, LP, Jenkins, DG, Holmberg, PM, and Kelly, VG. Effects of repeated jump testing and diurnal changes on subsequent countermovement jump and squat jump output and force-time characteristics. J Strength Cond Res 38(1): 174-179, 2024-The aim of this brief study was to investigate the effects of repeated jump testing on performance over 2 consecutive days while considering the possibility of diurnal changes. Fourteen male subjects and 14 recreationally active female subjects completed countermovement jump (CMJ) and squat jump (SJ) testing on 5 occasions (baseline [0,800], 5 minutes [0,820], 8 hours [1,600], 24 hours [0,800], and 32 hours [1,600]) over 32 hours. An additional rested baseline test was conducted on a separate day in the afternoon (1,600) to compare jump performance between morning and afternoon baseline values. Excluding small decreases in CMJ height at 24 hours (p = 0.292, Cliff's delta = -0.225) in male subjects and similar decreases in CMJ height at 5 minutes (p = 0.034, Cliff's delta = -0.245) in addition to SJ height:contraction time at 32 hours (p = 0.126, Cliff's delta = 0.153) in female subjects, findings generally showed no changes in jump performance over multiple assessments. Squat jump metrics may have showed small improvements between morning and afternoon baseline values in male subjects (SJ height:contraction time [p = 0.030, Cliff's delta = 0.225]) and female subjects (SJ height [p = 0.013, Cliff's delta = 0.173] and SJ height:contraction time [p = 0.091, Cliff's delta = 0.163)]. As jump performance was largely unaffected by repeated jump testing, the present findings support the use of monitoring practices and research designs that require multiple jump assessments within acute periods (∼32 hours).


Athletic Performance , Posture , Humans , Male , Female , Muscle Strength
18.
Eur J Med Chem ; 265: 116097, 2024 Feb 05.
Article En | MEDLINE | ID: mdl-38157595

Tridecaptins comprise a class of linear cationic lipopeptides with an N-terminal fatty acyl moiety. These 13-mer antimicrobial peptides consist of a combination of d- and l-amino acids, conferring increased proteolytic stability. Intriguingly, they are biosynthesized by non-ribosomal peptide synthetases in the same bacterial species that also produce the cyclic polymyxins displaying similar fatty acid tails. Previously, the des-acyl analog of TriA1 (termed H-TriA1) was found to possess very weak antibacterial activity, albeit it potentiated the effect of several antibiotics. In the present study, two series of des-acyl tridecaptins were explored with the aim of improving the direct antibacterial effect. At the same time, overall physico-chemical properties were modulated by amino acid substitution(s) to diminish the risk of undesired levels of hemolysis and to avoid an impairment of mammalian cell viability, since these properties are typically associated with highly hydrophobic cationic peptides. Microbiology and biophysics tools were used to determine bacterial uptake, while circular dichroism and isothermal calorimetry were used to probe the mode of action. Several analogs had improved antibacterial activity (as compared to that of H-TriA1) against Enterobacteriaceae. Optimization enabled identification of the lead compound 29 that showed a good ADMET profile as well as in vivo efficacy in a variety of mouse models of infection.


Anti-Bacterial Agents , Bacteria , Peptides , Animals , Mice , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Fatty Acids/chemistry , Lipopeptides/pharmacology , Lipopeptides/chemistry , Mammals , Microbial Sensitivity Tests , Cations/chemistry
19.
medRxiv ; 2023 Oct 05.
Article En | MEDLINE | ID: mdl-37873312

INTRODUCTION: Detection of Alzheimer's disease (AD) pathophysiology among cognitively unimpaired individuals and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma p-tau217 is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited. METHODS: We employed a novel p-tau217 immunoassay (UGOT p-tau217) in four independent cohorts (n=308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (ß-AARC). RESULTS: UGOT p-tau217 showed high accuracy (AUC= 0.80-0.91) identifying Aß pathology, determined either by Aß positron emission tomography or CSF Aß42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aß42/40 ratio (AUC= 0.91). DISCUSSION: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.

20.
J Strength Cond Res ; 37(11): e581-e587, 2023 Nov 01.
Article En | MEDLINE | ID: mdl-37883407

ABSTRACT: Harrison, PW, Kelly, VG, Jenkins, DG, McGuigan, MR, Holmberg, PM, and James, LP. Does moderate-load priming activity influence maximal upper-body performance and perceptual state?. J Strength Cond Res 37(11): e581-e587, 2023-The results of previous research indicate that resistance exercise "priming" may improve strength-power measures within 48 hours after their completion. Although researchers have primarily examined performance responses after lower-body priming stimuli, investigations examining the effects of upper-body resistance priming exercises are presently limited. Therefore, the aim of this study was to examine upper-body pushing and pulling performance in addition to perceptual responses 3 and 27 hours after moderate-load (ML) upper-body resistance priming exercise. Fourteen resistance-trained men were assigned to complete ML priming (4 × 3 bench press and bench pull at 65% 1RM [repetition maximum]) and control (rest) protocols in a randomized and counterbalanced order. Peak velocity during the bench throw and bench pull tests involving different loads (25, 50, and 75% 1RM) showed no practical change at 3 and 27 hours after the priming session (p = 0.216-0.99, Cliff's d = -0.041 to 0.225). Small effect size increases in perceptual measures ("physical feeling," "physical performance," "aggression" [p = 0.400-0.553, Cliff's d = 0.183-0.201], and "muscular heaviness" [p = 0.178, Cliff's d = 0.231]) were found at 3 hours postpriming. A moderate practical increase was observed in perceived "physical feeling" compared with control (p = 0.385, Cliff's d = 0.349) in addition to small effect size increases in perceived "physical performance" and "aggression" (Cliff's d = 0.243-0.290) at 27 hours after priming activities. These results indicate that upper-body strength-power changes within 27 hours after ML upper-body resistance exercise priming are not practically meaningful.


Muscle Strength , Resistance Training , Male , Humans , Muscle Strength/physiology , Resistance Training/methods , Exercise/physiology , Exercise Therapy , Weight Lifting/physiology , Muscle, Skeletal/physiology
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