Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study

BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients

From the cell membrane to the nucleus: unearthing transport mechanisms for Dynein

Mutations in the motor protein cytoplasmic dynein have been found to cause Charcot-Marie-Tooth disease, spinal muscular atrophy, and severe intellectual disabilities in humans. In mouse models, neurodegeneration is observed. We sought to develop a novel model which could incorporate the effects of mutations on distance travelled and velocity. A mechanical model for the dynein mediated transport of endosomes is derived from first principles and solved numerically. The effects of variations in model parameter values are analysed to find those that have a significant impact on velocity and distance travelled. The model successfully describes the processivity of dynein and matches qualitatively the velocity profiles observed in experiments

The Exact Correspondence between Phase Times and Dwell Times in a Symmetrical Quantum Tunneling Configuration

The general and explicit relation between the phase time and the dwell time for quantum tunneling or scattering is investigated. Considering a symmetrical collision of two identical wave packets with an one-dimensional barrier, here we demonstrate that these two distinct transit time definitions give connected results where, however, the phase time (group delay) accurately describes the exact position of the scattered particles. The analytical difficulties that arise when the stationary phase method is employed for obtaining phase (traversal) times are all overcome. Multiple wave packet decomposition allows us to recover the exact position of the reflected and transmitted waves in terms of the phase time, which, in addition to the exact relation between the phase time and the dwell time, leads to right interpretation for both of them.Comment: 11 pages, 2 figure

Small Corrections to the Tunneling Phase Time Formulation

After reexamining the above barrier diffusion problem where we notice that the wave packet collision implies the existence of {\em multiple} reflected and transmitted wave packets, we analyze the way of obtaining phase times for tunneling/reflecting particles in a particular colliding configuration where the idea of multiple peak decomposition is recovered. To partially overcome the analytical incongruities which frequently rise up when the stationary phase method is adopted for computing the (tunneling) phase time expressions, we present a theoretical exercise involving a symmetrical collision between two identical wave packets and a unidimensional squared potential barrier where the scattered wave packets can be recomposed by summing the amplitudes of simultaneously reflected and transmitted wave components so that the conditions for applying the stationary phase principle are totally recovered. Lessons concerning the use of the stationary phase method are drawn.Comment: 14 pages, 3 figure

An antibody-based biomarker discovery method by mass spectrometry sequencing of complementarity determining regions

Autoantibodies are increasingly used as biomarkers in the detection of autoimmune disorders and cancer. Disease specific antibodies are generally detected by their binding to specific antigens. As an alternative approach, we propose to identify specific complementarity determining regions (CDR) of IgG that relate to an autoimmune disorder or cancer instead of the specific antigen(s). In this manuscript, we tested the technical feasibility to detect and identify CDRs of specific antibodies by mass spectrometry. We used a commercial pooled IgG preparation as well as purified serum IgG fractions that were spiked with different amounts of a fully human monoclonal antibody (adalimumab). These samples were enzymatically digested and analyzed by nanoLC Orbitrap mass spectrometry. In these samples, we were able to identify peptides derived from the CDRs of adalimumab. These peptides could be detected at an amount of 110 attomole, 5 orders of magnitude lower than the total IgG concentration in these samples. Using higher energy collision induced dissociation (HCD) fragmentation and subsequent de novo sequencing, we could successfully identify 50% of the detectable CDR peptides of adalimumab. In addition, we demonstrated that an affinity purification with anti-dinitrophenol (DNP) monoclonal antibody enhanced anti-DNP derived CDR detection in a serum IgG background. In conclusion, specific CDR peptides could be detected and sequenced at relatively low levels (attomole-femtomole range) which should allow the detection of clinically relevant CDR peptides in patient samples

Foraging Behavior under Starvation Conditions Is Altered via Photosynthesis by the Marine Gastropod, Elysia clarki

It has been well documented that nutritional state can influence the foraging behavior of animals. However, photosynthetic animals, those capable of both heterotrophy and symbiotic photosynthesis, may have a delayed behavioral response due to their ability to photosynthesize. To test this hypothesis we subjected groups of the kleptoplastic sea slug, Elysia clarki, to a gradient of starvation treatments of 4, 8, and 12 weeks plus a satiated control. Compared to the control group, slugs starved 8 and 12 weeks displayed a significant increase in the proportion of slugs feeding and a significant decrease in photosynthetic capability, as measured in maximum quantum yield and [chl a]. The 4 week group, however, showed no significant difference in feeding behavior or in the metrics of photosynthesis compared to the control. This suggests that photosynthesis in E. clarki, thought to be linked to horizontally-transferred algal genes, delays a behavioral response to starvation. This is the first demonstration of a link between photosynthetic capability in an animal and a modification of foraging behavior under conditions of starvation

Training attention control of very preterm infants: protocol for a feasibility study of the Attention Control Training (ACT)

Background Children born preterm may display cognitive, learning, and behaviour difficulties as they grow up. In particular, very premature birth (gestation age between 28 and less than 32 weeks) may put infants at increased risk of intellectual deficits and attention deficit disorder. Evidence suggests that the basis of these problems may lie in difficulties in the development of executive functions. One of the earliest executive functions to emerge around 1 year of age is the ability to control attention. An eye-tracking-based cognitive training programme to support this emerging ability, the Attention Control Training (ACT), has been developed and tested with typically developing infants. The aim of this study is to investigate the feasibility of using the ACT with healthy very preterm (VP) infants when they are 12 months of age (corrected age). The ACT has the potential to address the need for supporting emerging cognitive abilities of VP infants with an early intervention, which may capitalise on infants’ neural plasticity. Methods/design The feasibility study is designed to investigate whether it is possible to recruit and retain VP infants and their families in a randomised trial that compares attention and social attention of trained infants against those that are exposed to a control procedure. Feasibility issues include the referral/recruitment pathway, attendance, and engagement with testing and training sessions, completion of tasks, retention in the study, acceptability of outcome measures, quality of data collected (particularly, eye-tracking data). The results of the study will inform the development of a larger randomised trial. Discussion Several lines of evidence emphasise the need to support emerging cognitive and learning abilities of preterm infants using early interventions. However, early interventions with preterm infants, and particularly very preterm ones, face difficulties in recruiting and retaining participants. These problems are also augmented by the health vulnerability of this population. This feasibility study will provide the basis for informing the implementation of an early cognitive intervention for very preterm infants. Trial registration Registered Registration ID: NCT03896490. Retrospectively registered at Clinical Trials Protocol Registration and Results System (clinicaltrials.gov)