Giant stem tetrapod was apex predator in Gondwanan late Palaeozoic ice age.

Current hypotheses of early tetrapod evolution posit close ecological and biogeographic ties to the extensive coal-producing wetlands of the Carboniferous palaeoequator with rapid replacement of archaic tetrapod groups by relatives of modern amniotes and lissamphibians in the late Carboniferous (about 307 million years ago). These hypotheses draw on a tetrapod fossil record that is almost entirely restricted to palaeoequatorial Pangea (Laurussia)1,2. Here we describe a new giant stem tetrapod, Gaiasia jennyae, from high-palaeolatitude (about 55° S) early Permian-aged (about 280 million years ago) deposits in Namibia that challenges this scenario. Gaiasia is represented by several large, semi-articulated skeletons characterized by a weakly ossified skull with a loosely articulated palate dominated by a broad diamond-shaped parasphenoid, a posteriorly projecting occiput, and enlarged, interlocking dentary and coronoid fangs. Phylogenetic analysis resolves Gaiasia within the tetrapod stem group as the sister taxon of the Carboniferous Colosteidae from Euramerica. Gaiasia is larger than all previously described digited stem tetrapods and provides evidence that continental tetrapods were well established in the cold-temperate latitudes of Gondwana during the final phases of the Carboniferous-Permian deglaciation. This points to a more global distribution of continental tetrapods during the Carboniferous-Permian transition and indicates that previous hypotheses of global tetrapod faunal turnover and dispersal at this time2,3 must be reconsidered.

Multifunctional biocatalyst for conjugate reduction and reductive amination.

Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals1, yet their preparation often relies on low-efficiency multi-step synthesis2. These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein we characterize a multifunctional biocatalyst for amine synthesis, which operates using a mechanism that is, to our knowledge, previously unreported. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,ß-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers bearing up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED, which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.

A dense 0.1-solar-mass star in a 51-minute-orbital-period eclipsing binary.

Of more than a thousand known cataclysmic variables (CVs), where a white dwarf is accreting from a hydrogen-rich star, only a dozen have orbital periods below 75 minutes1-9. One way to achieve these short periods requires the donor star to have undergone substantial nuclear evolution before interacting with the white dwarf10-14, and it is expected that these objects will transition to helium accretion. These transitional CVs have been proposed as progenitors of helium CVs13-18. However, no known transitional CV is expected to reach an orbital period short enough to account for most of the helium CV population, leaving the role of this evolutionary pathway unclear. Here we report observations of ZTF J1813+4251, a 51-minute-orbital-period, fully eclipsing binary system consisting of a star with a temperature comparable to that of the Sun but a density 100 times greater owing to its helium-rich composition, accreting onto a white dwarf. Phase-resolved spectra, multi-band light curves and the broadband spectral energy distribution allow us to obtain precise and robust constraints on the masses, radii and temperatures of both components. Evolutionary modelling shows that ZTF J1813+4251 is destined to become a helium CV binary, reaching an orbital period under 20 minutes, rendering ZTF J1813+4251 a previously missing link between helium CV binaries and hydrogen-rich CVs.

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.

BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).

Femtosecond-to-millisecond structural changes in a light-driven sodium pump.

Light-driven sodium pumps actively transport small cations across cellular membranes1. These pumps are used by microorganisms to convert light into membrane potential and have become useful optogenetic tools with applications in neuroscience. Although the resting state structures of the prototypical sodium pump Krokinobacter eikastus rhodopsin 2 (KR2) have been solved2,3, it is unclear how structural alterations over time allow sodium to be translocated against a concentration gradient. Here, using the Swiss X-ray Free Electron Laser4, we have collected serial crystallographic data at ten pump-probe delays from femtoseconds to milliseconds. High-resolution structural snapshots throughout the KR2 photocycle show how retinal isomerization is completed on the femtosecond timescale and changes the local structure of the binding pocket in the early nanoseconds. Subsequent rearrangements and deprotonation of the retinal Schiff base open an electrostatic gate in microseconds. Structural and spectroscopic data, in combination with quantum chemical calculations, indicate that a sodium ion binds transiently close to the retinal within one millisecond. In the last structural intermediate, at 20 milliseconds after activation, we identified a potential second sodium-binding site close to the extracellular exit. These results provide direct molecular insight into the dynamics of active cation transport across biological membranes.

Nonspherical ultrasound microbubbles.

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

General relativistic orbital decay in a seven-minute-orbital-period eclipsing binary system.

General relativity1 predicts that short-orbital-period binaries emit considerable amounts of gravitational radiation. The upcoming Laser Interferometer Space Antenna2 (LISA) is expected to detect tens of thousands of such systems3 but few have been identified4, of which only one5 is eclipsing-the double-white-dwarf binary SDSS J065133.338+284423.37, which has an orbital period of 12.75 minutes. Here we report the discovery of an eclipsing double-white-dwarf binary system, ZTF J153932.16+502738.8, with an orbital period of 6.91 minutes. This system has an orbit so compact that the entire binary could fit within the diameter of the planet Saturn. The system exhibits a deep eclipse, and a double-lined spectroscopic nature. We see rapid orbital decay, consistent with that expected from general relativity. ZTF J153932.16+502738.8 is a strong source of gravitational radiation close to the peak of LISA's sensitivity, and we expect it to be detected within the first week of LISA observations, once LISA launches in approximately 2034.

Goldilocks and RNA: where Mg2+ concentration is just right.

Magnesium, the most abundant divalent cation in cells, catalyzes RNA cleavage but also promotes RNA folding. Because folding can protect RNA from cleavage, we predicted a 'Goldilocks landscape', with local maximum in RNA lifetime at Mg2+ concentrations required for folding. Here, we use simulation and experiment to discover an innate and sophisticated mechanism of control of RNA lifetime. By simulation we characterized RNA Goldilocks landscapes and their dependence on cleavage and folding parameters. Experiments with yeast tRNAPhe and the Tetrahymena ribozyme P4-P6 domain show that structured RNAs can inhabit Goldilocks peaks. The Goldilocks peaks are tunable by differences in folded and unfolded cleavage rate constants, Mg2+ binding cooperativity, and Mg2+ affinity. Different folding and cleavage parameters produce Goldilocks landscapes with a variety of features. Goldilocks behavior allows ultrafine control of RNA chemical lifetime, whereas non-folding RNAs do not display Goldilocks peaks of protection. In sum, the effects of Mg2+ on RNA persistence are expected to be pleomorphic, both protecting and degrading RNA. In evolutionary context, Goldilocks behavior may have been a selectable trait of RNA in an early Earth environment containing Mg2+ and other metals.

Transmission potential of human schistosomes can be driven by resource competition among snail intermediate hosts.

Predicting and disrupting transmission of human parasites from wildlife hosts or vectors remains challenging because ecological interactions can influence their epidemiological traits. Human schistosomes, parasitic flatworms that cycle between freshwater snails and humans, typify this challenge. Human exposure risk, given water contact, is driven by the production of free-living cercariae by snail populations. Conventional epidemiological models and management focus on the density of infected snails under the assumption that all snails are equally infectious. However, individual-level experiments contradict this assumption, showing increased production of schistosome cercariae with greater access to food resources. We built bioenergetics theory to predict how resource competition among snails drives the temporal dynamics of transmission potential to humans and tested these predictions with experimental epidemics and demonstrated consistency with field observations. This resource-explicit approach predicted an intense pulse of transmission potential when snail populations grow from low densities, i.e., when per capita access to resources is greatest, due to the resource-dependence of cercarial production. The experiment confirmed this prediction, identifying a strong effect of infected host size and the biomass of competitors on per capita cercarial production. A field survey of 109 waterbodies also found that per capita cercarial production decreased as competitor biomass increased. Further quantification of snail densities, sizes, cercarial production, and resources in diverse transmission sites is needed to assess the epidemiological importance of resource competition and support snail-based disruption of schistosome transmission. More broadly, this work illustrates how resource competition can sever the correspondence between infectious host density and transmission potential.

Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease.

Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

The Forces Generated by Agonist Muscles during Isometric Contractions Arise from Motor Unit Synergies.

The purpose of our study was to identify the low-dimensional latent components, defined hereafter as motor unit modes, underlying the discharge rates of the motor units in two knee extensors (vastus medialis and lateralis, eight men) and two hand muscles (first dorsal interossei and thenars, seven men and one woman) during submaximal isometric contractions. Factor analysis identified two independent motor unit modes that captured most of the covariance of the motor unit discharge rates. We found divergent distributions of the motor unit modes for the hand and vastii muscles. On average, 75% of the motor units for the thenar muscles and first dorsal interosseus were strongly correlated with the module for the muscle in which they resided. In contrast, we found a continuous distribution of motor unit modes spanning the two vastii muscle modules. The proportion of the muscle-specific motor unit modes was 60% for vastus medialis and 45% for vastus lateralis. The other motor units were either correlated with both muscle modules (shared inputs) or belonged to the module for the other muscle (15% for vastus lateralis). Moreover, coherence of the discharge rates between motor unit pools was explained by the presence of shared synaptic inputs. In simulations with 480 integrate-and-fire neurons, we demonstrate that factor analysis identifies the motor unit modes with high levels of accuracy. Our results indicate that correlated discharge rates of motor units that comprise motor unit modes arise from at least two independent sources of common input among the motor neurons innervating synergistic muscles.SIGNIFICANCE STATEMENT It has been suggested that the nervous system controls synergistic muscles by projecting common synaptic inputs to the engaged motor neurons. In our study, we reduced the dimensionality of the output produced by pools of synergistic motor neurons innervating the hand and thigh muscles during isometric contractions. We found two neural modules, each representing a different common input, that were each specific for one of the muscles. In the vastii muscles, we found a continuous distribution of motor unit modes spanning the two synergistic muscles. Some of the motor units from the homonymous vastii muscle were controlled by the dominant neural module of the other synergistic muscle. In contrast, we found two distinct neural modules for the hand muscles.

Motor unit modes in the calf muscles during a submaximal isometric contraction are changed by brief stretches.

The purpose of our study was to investigate the influence of a stretch intervention on the common modulation of discharge rate among motor units in the calf muscles during a submaximal isometric contraction. The current report comprises a computational analysis of a motor unit dataset that we published previously (Mazzo et al., 2021). Motor unit activity was recorded from the three main plantar flexor muscles while participants performed an isometric contraction at 10% of the maximal voluntary contraction force before and after each of two interventions. The interventions were a control task (standing balance) and static stretching of the plantar flexor muscles. A factorization analysis on the smoothed discharge rates of the motor units from all three muscles yielded three modes that were independent of the individual muscles. The composition of the modes was not changed by the standing-balance task, whereas the stretching exercise reduced the average correlation in the second mode and increased it in the third mode. A centroid analysis on the correlation values showed that most motor units were associated with two or three modes, which were presumed to indicate shared synaptic inputs. The percentage of motor units adjacent to the seven centroids changed after both interventions: Control intervention, mode 1 decreased and the shared mode 1 + 2 increased; stretch intervention, shared modes either decreased (1 + 2) or increased (1 + 3). These findings indicate that the neuromuscular adjustments during both interventions were sufficient to change the motor unit modes when the same task was performed after each intervention. KEY POINTS: Based on covariation of the discharge rates of motor units in the calf muscles during a submaximal isometric contraction, factor analysis was used to assign the correlated discharge trains to three motor unit modes. The motor unit modes were determined from the combined set of all identified motor units across the three muscles before and after each participant performed a control and a stretch intervention. The composition of the motor unit modes changed after the stretching exercise, but not after the control task (standing balance). A centroid analysis on the distribution of correlation values found that most motor units were associated with a shared centroid and this distribution, presumably reflecting shared synaptic input, changed after both interventions. Our results demonstrate how the distribution of multiple common synaptic inputs to the motor neurons innervating the plantar flexor muscles changes after a brief series of stretches.

Small Warriors of Nature: Novel Red Emissive Chlorophyllin Carbon Dots Harnessing Fenton-Fueled Ferroptosis for In Vitro and In Vivo Cancer Treatment.

The appeal of carbon dots (CDs) has grown recently, due to their established biocompatibility, adjustable photoluminescence properties, and excellent water solubility. For the first time in the literature, copper chlorophyllin-based carbon dots (Chl-D CDs) are successfully synthesized. Chl-D CDs exhibit unique spectroscopic traits and are found to induce a Fenton-like reaction, augmenting photodynamic therapy (PDT) efficacies via ferroptotic and apoptotic pathways. To bolster the therapeutic impact of Chl-D CDs, a widely used cancer drug, temozolomide, is linked to their surface, yielding a synergistic effect with PDT and chemotherapy. Chl-D CDs' biocompatibility in immune cells and in vivo models showed great clinical potential.Proteomic analysis was conducted to understand Chl-D CDs' underlying cancer treatment mechanism. The study underscores the role of reactive oxygen species formation and pointed toward various oxidative stress modulators like aldolase A (ALDOA), aldolase C (ALDOC), aldehyde dehydrogenase 1B1 (ALDH1B1), transaldolase 1 (TALDO1), and transketolase (TKT), offering a deeper understanding of the Chl-D CDs' anticancer activity. Notably, the Chl-D CDs' capacity to trigger a Fenton-like reaction leads to enhanced PDT efficiencies through ferroptotic and apoptotic pathways. Hence, it is firmly believed that the inherent attributes of Chl-CDs can lead to a secure and efficient combined cancer therapy.

Sirenomelia: An anatomical assessment and genetic sex determination of two cases.

The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

Preclinical Evaluation of Zn(II) Self-Assemblies with Selective Cytotoxic Activity Against Cancer Cells In Vitro and In Ovo.

Dipodal pyridylthiazole amine ligands L1 and L2 both form different metallo-supramolecular self-assemblies with Zn2+ and Cu2+ and these are shown to be toxic and selective towards cancer cell lines in vitro. Furthermore, potency and selectivity are highly dependent upon the metal ions, ligand system and bound anion, with significant changes in chemosensitivity and selectivity dependent upon which species are employed. Importantly, significant anti-tumor activity was observed in ovo at doses that are non-toxic.

The influence of embolization of internal carotid artery aneurysms on arterial tortuosity: a prospective cohort study.

PURPOSE: To compare quantitative tortuosity descriptors of Internal Carotid Artery (ICA) on aneurysmal and non-aneurysmal side before and after embolization of aneurysm and to determine possible factors associated with its change. MATERIAL AND METHODS: An analysis of 52 patients with intracranial aneurysm, treated with endovascular procedure, was performed. Based on their Digital Subtraction Angiography images, obtained prior to the procedure and after first follow-up examination, tortuosity of ICA, both on the side of embolization and on the other side was analysed. For each patient tortuosity descriptors were calculated: Relative Length, Sum of Angle Metrics, Triangular Index, Product of Angle Distance, and Inflection Count Metric. To represent changes in tortuosity, for each descriptor delta value (Δ) was defined as value of the descriptor prior to embolization - value of the descriptor on follow-up examination. RESULTS: In the follow-up We found no statistically significant changes in tortuosity on non-embolized side. On the embolized side SOAM (2.89±0.92 vs. 2.38±0.94;p<0.001), PAD (5.01±1.83 vs. 3.95±1.72 ;p<0.001) and ICM (12.18±4.55 vs. 9.76±4.04 vs.;p = 0.006) was significantly higher after embolization than before embolization. Mean ΔRelative Length (-0.02 [-0.045--0.002] vs. -0.01 [-0.02-0.003];p - 0.003),ΔProduct of Angle Distance (0.84 [0.30 - 1.82] vs. 0.10 [-0.001 - 1.10];p<0.001) and ΔInflection Count Metric (2.05 [0.42 - 3.50] vs. 0.27 [0.02 - 2.16];p = 0.004) were significantly higher on the embolized side. CONCLUSION: Following study showed that embolization may increase the tortuosity of ICA.

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers.

BACKGROUND: The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. METHODS: Patients aged 50-74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. RESULTS: In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). CONCLUSION: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. TRIAL REGISTRATION: NCT03186989 since June 14, 2017.

Control of motor output during steady submaximal contractions is modulated by contraction history.

The purpose of the study was to investigate the influence of contraction history on force steadiness and the associated EMG activity during submaximal isometric contractions performed with the dorsiflexor muscles. The key feature of the protocol was a triangular ramp contraction performed in the middle of a steady contraction at a lower target force. The target force during the ramp contraction was 20% MVC greater than that during the steady contraction. Thirty-seven healthy individuals (21 men and 16 women) performed the submaximal tasks with the ankle dorsiflexors. Electromyography (EMG) signals were recorded from tibialis anterior with a pair of surface electrodes. The coefficient of variation for force was significantly greater during the second steady contraction compared with the first one at each of the seven target forces (p < 0.015; d = 0.38-0.92). Although the average applied force during the steady contractions before and after the triangular contraction was the same (p = 0.563), the mean EMG amplitude for the steady contractions performed after the triangular contraction was significantly greater at each of the seven target forces (p < 0.0001; d = 0.44-0.68). Also, there were significant differences in mean EMG frequency between the steady contractions performed before and after the triangular contraction (p < 0.01; d = 0.13-0.82), except at 10 and 20% MVC force. The greater force fluctuations during a steady submaximal contraction after an intervening triangular contraction indicate a change in the discharge characteristics of the involved motor units.

Explaining the influence of practice on the grooved pegboard times of older adults: role of force steadiness.

The purpose was to identify the variables that can explain the variance in the grooved pegboard times of older adults categorized as either fast or slow performers. Participants (n = 28; 60-83 years) completed two experimental sessions, before and after 6 practice sessions of the grooved pegboard test. The 2 groups were identified based on average pegboard times during the practice sessions. Average pegboard time during practice was 73 ± 11 s for the fast group and 85 ± 13 s for the slow group. Explanatory variables for the pegboard times before and after practice were the durations of 4 peg-manipulation phases and 12 measures of force steadiness (coefficient of variation [CV] for force) during isometric contractions with the index finger abductor and wrist extensor muscles. Time to complete the grooved pegboard test after practice decreased by 25 ± 11% for the fast group and by 28 ± 10% for the slow group. Multiple regression models explained more of the variance in the pegboard times for the fast group before practice (Adjusted R2 = 0.85) than after practice (R2 = 0.51), whereas the variance explained for the slow group was similar before (Adjusted R2 = 0.67) and after (Adjusted R2 = 0.64) practice. The explanatory variables differed between before and after practice for the fast group but only slightly for the slow group. These findings indicate that performance-based stratification of older adults can identify unique adjustments in motor function that are independent of chronological age.