Lipreading and Covert Speech Production Similarly Modulate Human Auditory-Cortex Responses to Pure Tones

Watching the lips of a speaker enhances speech perception. At the same time, the 100 ms response to speech sounds is suppressed in the observer's auditory cortex. Here, we used whole-scalp 306-channel magnetoencephalography (MEG) to study whether lipreading modulates human auditory processing already at the level of the most elementary sound features, i.e., pure tones. We further envisioned the temporal dynamics of the suppression to tell whether the effect is driven by top-down influences. Nineteen subjects were presented with 50 ms tones spanning six octaves (125–8000 Hz) (1) during “lipreading,” i.e., when they watched video clips of silent articulations of Finnish vowels /a/, /i/, /o/, and /y/, and reacted to vowels presented twice in a row; (2) during a visual control task; (3) during a still-face passive control condition; and (4) in a separate experiment with a subset of nine subjects, during covert production of the same vowels. Auditory-cortex 100 ms responses (N100m) were equally suppressed in the lipreading and covert-speech-production tasks compared with the visual control and baseline tasks; the effects involved all frequencies and were most prominent in the left hemisphere. Responses to tones presented at different times with respect to the onset of the visual articulation showed significantly increased N100m suppression immediately after the articulatory gesture. These findings suggest that the lipreading-related suppression in the auditory cortex is caused by top-down influences, possibly by an efference copy from the speech-production system, generated during both own speech and lipreading.Peer reviewe

A proposal for implementing an n-qubit controlled-rotation gate with three-level superconducting qubit systems in cavity QED

We present a way for implementing an n-qubit controlled-rotation gate with three-level superconducting qubit systems in cavity QED. The two logical states of a qubit are represented by the two lowest levels of each system while a higher-energy level is used for the gate implementation. The method operates essentially by preparing a $W$ state conditioned on the states of the control qubits, creating a single photon in the cavity mode, and then performing an arbitrary rotation on the states of the target qubit with assistance of the cavity photon. It is interesting to note that the basic operational steps for implementing the proposed gate do not increase with the number $n$ of qubits, and the gate operation time decreases as the number of qubits increases. This proposal is quite general, which can be applied to various types of superconducting devices in a cavity or coupled to a resonator.Comment: Six figures, accepted by Journal of Physics: Condensed Matte

Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A : A nationwide real-world study with 700 person-years

AimFor previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). MethodsFrom the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. ResultsAll 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (Europerkg) were 4391Euro (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448Euro (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. ConclusionsEarly high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.Peer reviewe

Generation of vortices and observation of Quantum Turbulence in an oscillating Bose-Einstein Condensate

We report on the experimental observation of vortex formation and production of tangled vortex distribution in an atomic BEC of Rb-87 atoms submitted to an external oscillatory perturbation. The oscillatory perturbations start by exciting quadrupolar and scissors modes of the condensate. Then regular vortices are observed finally evolving to a vortex tangle configuration. The vortex tangle is a signature of the presence of a turbulent regime in the cloud. We also show that this turbulent cloud has suppression of the aspect ratio inversion typically observed in quantum degenerate bosonic gases during free expansion.Comment: to appear in JLTP - QFS 200

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA

Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial

ObjectiveYKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission.MethodsNinety-nine patients with early DMARD-naive RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay.ResultsAt the baseline, plasma YKL-40 concentration was 57 +/- 37 ( mean +/- SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-alpha antagonist infliximab was added on the combination treatment.ConclusionsHigh YKL-40 levels were found to be associated with disease activity in early DMARD-naive RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission

Calculating Ensemble Averaged Descriptions of Protein Rigidity without Sampling

Previous works have demonstrated that protein rigidity is related to thermodynamic stability, especially under conditions that favor formation of native structure. Mechanical network rigidity properties of a single conformation are efficiently calculated using the integer body-bar Pebble Game (PG) algorithm. However, thermodynamic properties require averaging over many samples from the ensemble of accessible conformations to accurately account for fluctuations in network topology. We have developed a mean field Virtual Pebble Game (VPG) that represents the ensemble of networks by a single effective network. That is, all possible number of distance constraints (or bars) that can form between a pair of rigid bodies is replaced by the average number. The resulting effective network is viewed as having weighted edges, where the weight of an edge quantifies its capacity to absorb degrees of freedom. The VPG is interpreted as a flow problem on this effective network, which eliminates the need to sample. Across a nonredundant dataset of 272 protein structures, we apply the VPG to proteins for the first time. Our results show numerically and visually that the rigidity characterizations of the VPG accurately reflect the ensemble averaged properties. This result positions the VPG as an efficient alternative to understand the mechanical role that chemical interactions play in maintaining protein stability

Early start and stop of biologics: has the time come?

Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthriti

Identification, frequency, activation and function of CD4+ CD25highFoxP3+ regulatory T cells in children with juvenile idiopathic arthritis

The aim of the study was to test the frequency of CD4+ CD25highFoxP3 regulatory T cells in JIA patients and to assess their activation status and functional activity. The study involved 12 children with JIA and 35 healthy control subjects. PBMC were stained with monoclonal antibodies (anti-CD25, anti-CD4, anti-CD127, anti-CD69, anti-CD71, and anti-FoxP3). The samples were evaluated using flow cytometer. CD4+ CD25− and CD4+ CD25+ cells were isolated by negative and positive selection with magnetic microbeads. CD4+ CD25+ and CD4+ CD25− cells were cultured separately and co-cultured (1:1) with or without PHA. The percentage of Tregs in JIA patients was significantly decreased in comparison with controls (median, 3.2 vs. 4.6; P = 0.042). Relative fluorescence intensities of FoxP3 were higher in JIA patients than in controls (median, 9.1 vs. 6.8). The percentage of activated Tregs (CD71+) was significantly higher in JIA patients in comparison with controls (median, 6.5 vs. 2.8; P = 0.00043). CD4+ CD25+ cells derived from JIA patients and controls were anergic upon PHA stimulation, while CD4+ CD25− cells showed intensive proliferative response. The proliferation rate of CD4+ CD25− cells stimulated by PHA was decreased in co-cultures. In JIA patients, the inhibition of proliferation of CD4+ CD25− cells by CD4+ CD25+ cells was 37.9%, whereas in controls it was significantly lower (55.7%, P = 0.046). JIA patients had statistically lower percentage of Tregs in peripheral blood compared to controls. CD4+ CD25+ cells sorted from peripheral blood of JIA patients had statistically lower ability to suppress CD4+ CD25− cell proliferation in comparison with cells obtained from controls

Changes in Lysozyme Flexibility upon Mutation Are Frequent, Large and Long-Ranged

We investigate changes in human c-type lysozyme flexibility upon mutation via a Distance Constraint Model, which gives a statistical mechanical treatment of network rigidity. Specifically, two dynamical metrics are tracked. Changes in flexibility index quantify differences within backbone flexibility, whereas changes in the cooperativity correlation quantify differences within pairwise mechanical couplings. Regardless of metric, the same general conclusions are drawn. That is, small structural perturbations introduced by single point mutations have a frequent and pronounced affect on lysozyme flexibility that can extend over long distances. Specifically, an appreciable change occurs in backbone flexibility for 48% of the residues, and a change in cooperativity occurs in 42% of residue pairs. The average distance from mutation to a site with a change in flexibility is 17–20 Å. Interestingly, the frequency and scale of the changes within single point mutant structures are generally larger than those observed in the hen egg white lysozyme (HEWL) ortholog, which shares 61% sequence identity with human lysozyme. For example, point mutations often lead to substantial flexibility increases within the β-subdomain, which is consistent with experimental results indicating that it is the nucleation site for amyloid formation. However, β-subdomain flexibility within the human and HEWL orthologs is more similar despite the lowered sequence identity. These results suggest compensating mutations in HEWL reestablish desired properties