Derivative moments in turbulent shear flows

We propose a generalized perspective on the behavior of high-order derivative moments in turbulent shear flows by taking account of the roles of small-scale intermittency and mean shear, in addition to the Reynolds number. Two asymptotic regimes are discussed with respect to shear effects. By these means, some existing disagreements on the Reynolds number dependence of derivative moments can be explained. That odd-order moments of transverse velocity derivatives tend not vanish as expected from elementary scaling considerations does not necessarily imply that small-scale anisotropy persists at all Reynolds numbers.Comment: 11 pages, 7 Postscript figure

Longitudinal Structure Functions in Decaying and Forced Turbulence

In order to reliably compute the longitudinal structure functions in decaying and forced turbulence, local isotropy is examined with the aid of the isotropic expression of the incompressible conditions for the second and third order structure functions. Furthermore, the Karman-Howarth-Kolmogorov relation is investigated to examine the effects of external forcing and temporally decreasing of the second order structure function. On the basis of these investigations, the scaling range and exponents $\zeta_n$ of the longitudinal structure functions are determined for decaying and forced turbulence with the aid of the extended-self-similarity (ESS) method. We find that $\zeta_n$'s are smaller, for $n \geq 4$, in decaying turbulence than in forced turbulence. The reasons for this discrepancy are discussed. Analysis of the local slopes of the structure functions is used to justify the ESS method.Comment: 15 pages, 16 figure

Stable task information from an unstable neural population

Over days and weeks, neural activity representing an animal’s position and movement in sensorimotor cortex has been found to continually reconfigure or ‘drift’ during repeated trials of learned tasks, with no obvious change in behavior. This challenges classical theories, which assume stable engrams underlie stable behavior. However, it is not known whether this drift occurs systematically, allowing downstream circuits to extract consistent information. Analyzing long-term calcium imaging recordings from posterior parietal cortex in mice (Mus musculus), we show that drift is systematically constrained far above chance, facilitating a linear weighted readout of behavioral variables. However, a significant component of drift continually degrades a fixed readout, implying that drift is not confined to a null coding space. We calculate the amount of plasticity required to compensate drift independently of any learning rule, and find that this is within physiologically achievable bounds. We demonstrate that a simple, biologically plausible local learning rule can achieve these bounds, accurately decoding behavior over many days

Local properties of extended self-similarity in 3D turbulence

Using a generalization of extended self-similarity we have studied local scaling properties of 3D turbulence in a direct numerical simulation. We have found that these properties are consistent with lognormal-like behavior of energy dissipation fluctuations with moderate amplitudes for space scales $r$ beginning from Kolmogorov length $\eta$ up to the largest scales, and in the whole range of the Reynolds numbers: $50 \leq R_{\lambda} \leq 459$. The locally determined intermittency exponent $\mu(r)$ varies with $r$; it has a maximum at scale $r=14 \eta$, independent of $R_{\lambda}$.Comment: 4 pages, 5 figure

VCP suppresses proteopathic seeding in neurons

BACKGROUND: Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. METHODS: We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. RESULTS: One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. CONCLUSION: Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP\u27s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP

Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation

Aggregates of the RNA-binding protein TDP-43 (TAR DNAbinding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stage is primarily driven by TDP-43’s RNA-binding region. Specific binding to GU-rich RNA strongly inhibited both TDP-43 oligomerization and aggregation, suggesting that RNA interactions are critical for maintaining TDP-43 solubility. Moreover, we analyzed TDP-43 liquid–liquid phase separation and detected similar detergentresistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that aggregates generated from purified TDP-43 seed intracellular aggregation detected by established TDP-43 pathology markers. Remarkably, cytoplasmic aggregate seeding was detected earlier for the A315T and M337V variants and was 50% more widespread than forWTTDP-43 aggregates.We provide evidence for aninitial step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbationsin TDP-43 homeostasisin protein aggregation and ALS-FTD pathogenesis

Dynamical equations for high-order structure functions, and a comparison of a mean field theory with experiments in three-dimensional turbulence

Two recent publications [V. Yakhot, Phys. Rev. E {\bf 63}, 026307, (2001) and R.J. Hill, J. Fluid Mech. {\bf 434}, 379, (2001)] derive, through two different approaches that have the Navier-Stokes equations as the common starting point, a set of steady-state dynamic equations for structure functions of arbitrary order in hydrodynamic turbulence. These equations are not closed. Yakhot proposed a "mean field theory" to close the equations for locally isotropic turbulence, and obtained scaling exponents of structure functions and an expression for the tails of the probability density function of transverse velocity increments. At high Reynolds numbers, we present some relevant experimental data on pressure and dissipation terms that are needed to provide closure, as well as on aspects predicted by the theory. Comparison between the theory and the data shows varying levels of agreement, and reveals gaps inherent to the implementation of the theory.Comment: 16 pages, 23 figure

Statistics of Dissipation and Enstrophy Induced by a Set of Burgers Vortices

Dissipation and enstropy statistics are calculated for an ensemble of modified Burgers vortices in equilibrium under uniform straining. Different best-fit, finite-range scaling exponents are found for locally-averaged dissipation and enstrophy, in agreement with existing numerical simulations and experiments. However, the ratios of dissipation and enstropy moments supported by axisymmetric vortices of any profile are finite. Therefore the asymptotic scaling exponents for dissipation and enstrophy induced by such vortices are equal in the limit of infinite Reynolds number.Comment: Revtex (4 pages) with 4 postscript figures included via psfi

Erratum to 'Exploring the cost-effectiveness of high versus low perioperative fraction of inspired oxygen in the prevention of surgical site infections among abdominal surgery patients in three low- and middle-income countries' [BJA Open 7 (2023) 100207]

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Hughes Abdominal Repair Trial (HART) – Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial

Background Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The ‘Hughes Repair’ combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. Methods/design This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. Discussion A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions