Toftaaen5740

The molecules and mechanisms behind chemical synaptic transmission have been explored for decades. For several of the core proteins involved in synaptic vesicle fusion, we now have a reasonably detailed grasp of their biochemical, structural, and functional properties. Complexin is one of the key synaptic proteins for which a simple mechanistic understanding is still lacking. Living up to its name, this small protein has been associated with a variety of roles differing between synapses and between species, but little consensus has been reached on its fundamental modes of action. Much attention has been paid to its deeply conserved SNARE-binding properties, while membrane-binding features of complexin and their functional significance have yet to be explored to the same degree. In this review, we summarize the known membrane interactions of the complexin C-terminal domain and their potential relevance to its function, synaptic localization, and evolutionary history.Neuronal communication depends on exquisitely regulated membrane fusion between synaptic vesicles and presynaptic neurons, which results in neurotransmitter release in precisely timed patterns. Presynaptic dysfunctions are known to occur prior to the onset of neurodegenerative diseases, including Parkinson's disease. Synaptic accumulation of α-synuclein (α-Syn) oligomers has been implicated in the pathway leading to such outcomes. α-Syn oligomers exert aberrant effects on presynaptic fusion machinery through their interactions with synaptic vesicles and proteins. Here, we summarize in vitro bulk and single-vesicle assays for investigating the functions of α-Syn monomers and oligomers in synaptic vesicle fusion and then discuss the current understanding of the roles of α-Syn monomers and oligomers in synaptic vesicle fusion. Finally, we suggest a new therapeutic avenue specifically targeting the mechanisms of α-Syn oligomer toxicity rather than the oligomer itself.As a platform to deliver imaging and therapeutic agents to targeted sites in vivo, nanoparticles (NPs) have widespread applications in diagnosis and treatment of cancer. However, the poor in vivo delivery efficiency of nanoparticles limits its potential for further application. Once enter the physiological environment, nanoparticles immediately interact with proteins and form protein corona, which changes the physicochemical properties of nanoparticle surface and further affects their transport. In this study, we performed molecular dynamics simulations to study the adsorption mechanism of nanoparticles with various surface modifications and different proteins (e.g., human serum albumin, complement protein C3b), and their interactions with cell membrane. The results show that protein human serum albumin prefers to interact with hydrophobic and positively charged nanoparticles, while the protein C3b prefers the hydrophobic and charged nanoparticles. The pre-adsorption of human serum albumin on the nanoparticle surface obviously decreases the interaction of nanoparticle with C3b. Furthermore, the high amount of protein pre-adsorption could decrease the probability of nanoparticle-membrane interaction. These results indicate that appropriate modification of nanoparticles with protein provides nanoparticles with better capability of targeting, which could be used to guide nanoparticle design and improve transport efficiency.

Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury.

This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine.

Fifty patients were randomized, and 43 patients completed the study (IMGX003, n= 21; placebo, n= 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P= .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P= .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P= .231), 0.96 vs 3.29 (bloating, P= .204), and 0.02 vs 3.20 (tiredness, P= .113). The 3× 2-week trend line significance values for these symptoms, respectively, were P= .014, .030, and .002.

IMGX003 reduced gluten-induced intestinal mucosal damageand symptom severity. (ClinicalTrials.gov, Number NCT03585478).

IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number NCT03585478).

To support primary care physicians (PCPs) and their patients with knee osteoarthritis (OA), we created a series of evidence-based whiteboard educational videos for patients with knee OA. In a previous study we piloted these videos with patients to understand their acceptability and impact. The purpose of this study was to explore PCPs' perspectives to understand the utility of novel patient education videos to support management.

We conducted a qualitative descriptive study using semi-structured interviews of newly practicing and resident PCPs after watching a series of patient education videos. A thematic analysis approach was used combining both inductive and research question driven coding, category formation, and theme identification.

Ten participants were included. see more Barriers to optimal management were identified including the challenge of patient adherence and access to non-operative treatments. PCPs indicated that the videos would support their management of patients with knee OA by (1) supporting ers that may limit uptake is necessary and may optimize management of knee OA in primary care.IMPLICATIONS FOR REHABILITATIONThe provision of patient educational materials may support patient buy-in regarding appropriate management, enhance patient understanding, and improve physicians' future practice.Viewing these videos could potentially improve physicians' future resource use, recommendation of non-operative treatments, and the quality of their total knee replacement referrals, which has benefits to both the patient and the healthcare system.Perceived barriers to implementing evidence-based recommendations may pose a challenge for patients and clinicians and should be considered to help facilitate the uptake of educational interventions.

This systematic review and meta-analysis aimed to evaluate the effectiveness of inspiratory muscle training (IMT) on respiratory muscle strength, lung function and quality of life (QOL) in adults with spinal cord injuries (SCI).

Databases were searched up to June 2022; CENTRAL, CINAHL, MEDLINE, PEDRo, and PubMed. Following PRISMA reporting guidelines, two independent reviewers selected studies and extracted data. Study quality and levels of evidence were assessed.

Following selection from 624 initial search results, six randomised controlled trials were identified, comprising 124 participants. Quality of Evidence was very low to moderate. Meta-analysis showed that post intervention, IMT significantly improved maximal inspiratory pressure (MD 15.72 cmH2O, 95% CI 5.02, 26.41,

 = 0.004) when compared with a control intervention. There was no significant benefit for physical QOL (SMD 0.12, 95% CI -1.01, 1.25,

 = 0.84), mental QOL (SMD -0.2, 95% CI -1.72, 1.33,

 = 0.80), maximal expiratory pressure (MDring-loaded inspiratory threshold device may generate the largest improvements in respiratory strength.

There is increasing recognition that non-daily cigarette smoking is common in early adulthood but less is known about its stability over time, or what influences transitions to heavier or nonsmoking. We examined the stability of non-daily smoking in a sample of young adults, and tested whether social and cognitive factors predicted transitions to other smoking patterns over time.

Participants were 579 young adults (18-24 years old at enrollment, 52% male) who were non-daily and never-daily cigarette smokers and California residents. Participants completed 13 waves of assessment over 3 years. We used descriptive statistics to evaluate the frequency of consistent abstinence, defined as no cigarette use at two consecutive waves and no cigarette use at any subsequent waves. Cox and logistic regression were used to test predictors of consistent abstinence.

We found that 55% of participants smoked intermittently throughout the study, while 43% were consistently abstinent by the end of the study; few transitioho are non-daily cigarette smokers appear to maintain this habit over an extended period and may require intervention. Interventions that focus on reducing expectancies for positive effects of and social motives for cigarette use and on increasing intent to quit smoking may be most effective.

Artemisinin-resistant genotypes of Plasmodium falciparum have now emerged a minimum of six times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy. We aimed to model and evaluate the long-term effects of high levels of partner-drug resistance on the early emergence of artemisinin-resistant genotypes.

Using a consensus modelling approach, we used three individual-based mathematical models of Plasmodium falciparum transmission to evaluate the effects of pre-existing partner-drug resistance and ACT deployment on the evolution of artemisinin resistance. Each model simulates 100 000 individuals in a particular transmission setting (malaria prevalence of 1%, 5%, 10%, or 20%) with a daily time step that updates individuals' infection status, treatment status, immunity, genotype-sp resistance has the largest effect, with piperaquine resistance accelerating the early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.

Schmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.

Schmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.Paediatric acute liver failure (PALF) is defined as a biochemical evidence of acute liver injury in a child with no previous history of chronic liver disease characterised by an international normalised ratio (INR) of 1·5 or more unresponsive to vitamin K with encephalopathy, or INR of 2·0 or more with or without encephalopathy. PALF can rapidly progress to multiorgan dysfunction or failure. Although the transplant era has substantially changed the outlook for these patients, transplantation itself is not without risks, including those associated with life-long immunosuppression. Consequently, there has been an increased focus on improving medical management to prioritise bridging of patients to native liver survival, which is possible due to improved understanding of the underlying pathophysiology of multiorgan involvement in PALF. In this Review, we discuss recent advances in the medical management of PALF with an aim of reducing the need for liver transplantation. The Review will focus on the non-specific immune-mediated inflammatory response, extracorporeal support devices, neuromonitoring and neuroprotection, and emerging cellular and novel future therapeutic options.