Cognitive impairments in schizophrenia are associated with lower gamma oscillation power in the prefrontal cortex (PFC). Gamma power depends in part on excitatory drive to fast-spiking parvalbumin ...interneurons (PVIs). Excitatory drive to cortical neurons varies in strength, which could affect how these neurons regulate network oscillations. The authors investigated whether variability in excitatory synaptic strength across PVIs could contribute to lower prefrontal gamma power in schizophrenia.
In postmortem PFC from 20 matched pairs of comparison and schizophrenia subjects, levels of vesicular glutamate transporter 1 (VGlut1) and postsynaptic density 95 (PSD95) proteins were quantified to assess variability in excitatory synaptic strength across PVIs. A computational model network was then used to simulate how variability in excitatory synaptic strength across fast-spiking (a defining feature of PVIs) interneurons (FSIs) regulates gamma power.
The variability of VGlut1 and PSD95 levels at excitatory inputs across PVIs was larger in schizophrenia relative to comparison subjects. This alteration was not influenced by schizophrenia-associated comorbid factors, was not present in monkeys chronically exposed to antipsychotic medications, and was not present in calretinin interneurons. In the model network, variability in excitatory synaptic strength across FSIs regulated gamma power by affecting network synchrony. Finally, greater synaptic variability interacted synergistically with other synaptic alterations in schizophrenia (i.e., fewer excitatory inputs to FSIs and lower inhibitory strength from FSIs) to robustly reduce gamma power.
The study findings suggest that greater variability in excitatory synaptic strength across PVIs, in combination with other modest synaptic alterations in these neurons, can markedly lower PFC gamma power in schizophrenia.
To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector-based gene therapy for RPE65 mutation-associated inherited retinal dystrophy (IRD), including results of a ...phase 1 follow-on study at year 4 and phase 3 study at year 2.
Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial.
Forty subjects who received 1.5×10
vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention OI and 9 control/intervention CI).
Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects.
End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing.
Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log
(cd.s/m
) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred.
After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation-associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.
We reformulate gauge theories in analogy with the vierbein formalism of general relativity. More specifically, we reformulate gauge theories such that their gauge dynamical degrees of freedom are ...local fields that transform linearly under the dual representation of the charged matter field. These local fields, which naively have the interpretation of nonlocal operators similar to Wilson lines, satisfy constraint equations. A set of basis tensor fields is used to solve these constraint equations, and their field theory is constructed. A new local symmetry in terms of the basis tensor fields is used to make this field theory local and maintain a Hamiltonian that is bounded from below. The field theory of the basis tensor fields is what we call the basis tensor gauge theory.
To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation–associated inherited retinal dystrophy (IRD); describe the range of causative mutations; ...determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses.
Global, multicenter, retrospective chart review.
Study Population: Seventy individuals with biallelic RPE65 mutation–associated IRD. Procedures: Data were extracted from patient charts. Measurements: Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available).
VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships.
The number of clinical diagnoses and lack of a consistent RPE65 mutation–to–phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations.
Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in ...participants whose inherited retinal dystrophy would otherwise progress to complete blindness.
In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete.
Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity.
Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable.
Spark Therapeutics.
Colonic adenomatous polyposis of unknown etiology (CPUE) is an adenomatous polyposis phenotype that resembles Familial Adenomatous Polyposis (FAP) even though no germline pathogenic variant is ...identified.
We sought to better characterize the clinical features and outcomes in a cohort of CPUE patients.
This is a retrospective case series of patients 18 years old or older with aden-omatous oligopolyposis (between 10-100 adenomas) and negative genetic testing, identified through the Hereditary Gastrointestinal Cancer Database at Massachusetts General Hospital, a tertiary academic referral center. A retrospective chart review was performed with a focus on demographics, alcohol and tobacco use, medication use, familial malignancy and polyp burden, genetic testing information, endoscopic surveillance data including the corresponding histopathology, colonic and extracolonic malignancies, mortality events, and their etiology. Spearman correlation and Pearson Chi-square test (or Fisher's exact test) were used for continuous and categorical variables respectively.
CPUE patients were primarily male (69%) and presented for genetic counseling at 63.7 years. Only 2 patients (2.9%) reported a first-degree relative with polyposis. During an average surveillance period of 12.3 years, 0.5 colonoscopies
year were performed. Patients developed 2.3 new adenomas
year. 4 (5.7%) were diagnosed with colorectal cancer (CRC) at a mean age of 66 years, and 3 were diagnosed prior to the onset of oligopolyposis. 7 (10%) required colectomy due to advanced dysplasia or polyp burden. With respect to upper gastrointestinal manifestations, 1 patient had a gastric adenoma, but there were no cases of gastric or small bowel polyposis. During surveillance, 10 (14%) patients died at a mean age of 72, and none were due to CRC.
CPUE is distinct from familial adenomatous polyposis (FAP) syndrome and the use of FAP surveillance guidelines may result in unnecessarily frequent upper and lower endoscopies.
In thermal convection for very large Rayleigh numbers (
$Ra$
), the thermal and viscous boundary layers are expected to undergo a transition from a classical state to an ultimate state. In the former ...state, the boundary-layer thicknesses follow a laminar-like Prandtl–Blasius–Polhausen scaling, whereas in the latter, the boundary layers are turbulent with logarithmic corrections in the sense of Prandtl and von Kármán. Here, we report evidence of this transition via changes in the boundary-layer structure of vertical natural convection (VC), which is a buoyancy-driven flow between differentially heated vertical walls. The numerical dataset spans
$Ra$
values from
$10^{5}$
to
$10^{9}$
and a constant Prandtl number value of
$0.709$
. For this
$Ra$
range, the VC flow has been previously found to exhibit classical state behaviour in a global sense. Yet, with increasing
$Ra$
, we observe that near-wall higher-shear patches occupy increasingly larger fractions of the wall areas, which suggest that the boundary layers are undergoing a transition from the classical state to the ultimate shear-dominated state. The presence of streaky structures – reminiscent of the near-wall streaks in canonical wall-bounded turbulence – further supports the notion of this transition. Within the higher-shear patches, conditionally averaged statistics yield a logarithmic variation in the local mean temperature profiles, in agreement with the log law of the wall for mean temperature, and an
$Ra^{0.37}$
effective power-law scaling of the local Nusselt number. The scaling of the latter is consistent with the logarithmically corrected
$1/2$
power-law scaling predicted for ultimate thermal convection for very large
$Ra$
. Collectively, the results from this study indicate that turbulent and laminar-like boundary layer coexist in VC at moderate to high
$Ra$
and this transition from the classical state to the ultimate state manifests as increasingly larger shear-dominated patches, consistent with the findings reported for Rayleigh–Bénard convection and Taylor–Couette flows.
Climate Data Records of soil moisture are fundamental for improving our understanding of long-term dynamics in the coupled water, energy, and carbon cycles over land. To respond to this need, in 2012 ...the European Space Agency (ESA) released the first multi-decadal, global satellite-observed soil moisture (SM) dataset as part of its Climate Change Initiative (CCI) program. This product, named ESA CCI SM, combines various single-sensor active and passive microwave soil moisture products into three harmonised products: a merged ACTIVE, a merged PASSIVE, and a COMBINED active+passive microwave product. Compared to the first product release, the latest version of ESA CCI SM includes a large number of enhancements, incorporates various new satellite sensors, and extends its temporal coverage to the period 1978–2015. In this study, we first provide a comprehensive overview of the characteristics, evolution, and performance of the ESA CCI SM products. Based on original research and a review of existing literature we show that the product quality has steadily increased with each successive release and that the merged products generally outperform the single-sensor input products. Although ESA CCI SM generally agrees well with the spatial and temporal patterns estimated by land surface models and observed in-situ, we identify surface conditions (e.g., dense vegetation, organic soils) for which it still has large uncertainties. Second, capitalising on the results of >100 research studies that made use of the ESA CCI SM data we provide a synopsis of how it has contributed to improved process understanding in the following Earth system domains: climate variability and change, land-atmosphere interactions, global biogeochemical cycles and ecology, hydrological and land surface modelling, drought applications, and meteorology. While in some disciplines the use of ESA CCI SM is already widespread (e.g. in the evaluation of model soil moisture states) in others (e.g. in numerical weather prediction or flood forecasting) it is still in its infancy. The latter is partly related to current shortcomings of the product, e.g., the lack of near-real-time availability and data gaps in time and space. This study discloses the discrepancies between current ESA CCI SM product characteristics and the preferred characteristics of long-term satellite soil moisture products as outlined by the Global Climate Observing System (GCOS), and provides important directions for future ESA CCI SM product improvements to bridge these gaps.
•State-of-the-art of the ESA CCI soil moisture (ESA CCI SM) product specifications•A comprehensive assessment of the ESA CCI SM error characteristics•A unique synthesis of studies using ESA CCI SM to improve Earth system understanding.•Identification of future algorithmic and programmatic priorities
Simulations and experiments at low Reynolds numbers have suggested that skin-friction drag generated by turbulent fluid flow over a surface can be decreased by oscillatory motion in the surface, with ...the amount of drag reduction predicted to decline with increasing Reynolds number. Here, we report direct measurements of substantial drag reduction achieved by using spanwise surface oscillations at high friction Reynolds numbers (Formula: see text) up to 12,800. The drag reduction occurs via two distinct physical pathways. The first pathway, as studied previously, involves actuating the surface at frequencies comparable to those of the small-scale eddies that dominate turbulence near the surface. We show that this strategy leads to drag reduction levels up to 25% at Formula: see text = 6,000, but with a power cost that exceeds any drag-reduction savings. The second pathway is new, and it involves actuation at frequencies comparable to those of the large-scale eddies farther from the surface. This alternate pathway produces drag reduction of 13% at Formula: see text = 12,800. It requires significantly less power and the drag reduction grows with Reynolds number, thereby opening up potential new avenues for reducing fuel consumption by transport vehicles and increasing power generation by wind turbines.
To date, the understanding of the role buoyancy plays in the entrainment process in unstable configurations such as turbulent plumes remains incomplete. Towards addressing this question, we set up a ...flow in which a plume evolves in time instead of space. We demonstrate that the temporal problem is equivalent to a spatial plume in a strong coflow and address in detail how the temporal plume can be realized via direct numerical simulation. Using numerical data of plume simulations up to
$Re_{\unicodeSTIX{x1D706}}\approx 100$
, we show that the entrainment coefficient can be determined consistently using a global entrainment analysis in an integral framework as well as via a local approach. The latter is based on a study of the local propagation of the turbulent/non-turbulent interface relative to the fluid. Locally, this process is dominated by small-scale diffusion which is amplified by interface convolutions such that the total entrained flux is independent of viscosity. Further, we identify a direct buoyancy contribution to entrainment by baroclinic torque, which accounts for 8 %–12 % of the entrained flux locally, comparable to the 15 % buoyancy contribution at the integral level. It appears that the baroclinic torque is a mechanism that might explain higher values of the entrainment coefficient in spatial plumes compared with jets.
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