Atopic dermatitis (AD) is a common allergic skin disease, characterized by dryness, itchiness, thickening and inflammation of the skin. Infiltration of eosinophils into the dermal layer and presence ...of edema are typical characteristics in the skin biopsy of AD patients. Previous in vitro and clinical studies showed that the Pentaherbs formula (PHF) consisting of five traditional Chinese herbal medicines, Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis at w/w ratio of 2:1:2:2:2 exhibited therapeutic potential in treating AD. In this study, an in vivo murine model with oxazolone (OXA)-mediated dermatitis was used to elucidate the efficacy of PHF. Active ingredients of PHF water extract were also identified and quantified, and their in vitro anti-inflammatory activities on pruritogenic cytokine IL-31- and alarmin IL-33-activated human eosinophils and dermal fibroblasts were evaluated. Ear swelling, epidermis thickening and eosinophils infiltration in epidermal and dermal layers, and the release of serum IL-12 of the murine OXA-mediated dermatitis were significantly reduced upon oral or topical treatment with PHF (all p < 0.05). Gallic acid, chlorogenic acid and berberine contents (w/w) in PHF were found to be 0.479%, 1.201% and 0.022%, respectively. Gallic acid and chlorogenic acid could suppress the release of pro-inflammatory cytokine IL-6 and chemokine CCL7 and CXCL8, respectively, in IL-31- and IL-33-treated eosinophils-dermal fibroblasts co-culture; while berberine could suppress the release of IL-6, CXCL8, CCL2 and CCL7 in the eosinophil culture and eosinophils-dermal fibroblasts co-culture (all p < 0.05). These findings suggest that PHF can ameliorate allergic inflammation and attenuate the activation of eosinophils.
The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G1/S or G2/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by ...initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death.
Intrinsically disordered regions of proteins play an essential role in the regulation of various biological processes. Key to their regulatory function is often the binding to globular protein ...domains via sequence elements known as molecular recognition features (MoRFs). Development of computational tools for the identification of candidate MoRF locations in amino acid sequences is an important task and an area of growing interest. Given the relative sparseness of MoRFs in protein sequences, the accuracy of the available MoRF predictors is often inadequate for practical usage, which leaves a significant need and room for improvement. In this work, we introduce MoRFCHiBi_Web, which predicts MoRF locations in protein sequences with higher accuracy compared to current MoRF predictors.
Three distinct and largely independent property scores are computed with component predictors and then combined to generate the final MoRF propensity scores. The first score reflects the likelihood of sequence windows to harbour MoRFs and is based on amino acid composition and sequence similarity information. It is generated by MoRFCHiBi using small windows of up to 40 residues in size. The second score identifies long stretches of protein disorder and is generated by ESpritz with the DisProt option. Lastly, the third score reflects residue conservation and is assembled from PSSM files generated by PSI-BLAST. These propensity scores are processed and then hierarchically combined using Bayes rule to generate the final MoRFCHiBi_Web predictions.
MoRFCHiBi_Web was tested on three datasets. Results show that MoRFCHiBi_Web outperforms previously developed predictors by generating less than half the false positive rate for the same true positive rate at practical threshold values. This level of accuracy paired with its relatively high processing speed makes MoRFCHiBi_Web a practical tool for MoRF prediction.
http://morf.chibi.ubc.ca:8080/morf/.
There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions ...that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.
Cortical development depends on the active integration of cell-autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex ...protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions.
► Embryonic CSF distributes many factors to the developing brain ► CSF Igf2 binds to progenitors and stimulates their proliferation ► Pals1 and Pten regulate Igf1 receptor expression ► Igf2 in glioblastoma CSF regulates progenitor proliferation and disease state
ObjectivesPrevention of falls and fall-related injuries is a priority due to the substantial health and financial burden of falls on patients and healthcare systems. Deprescribing medications known ...as ‘fall-risk increasing drugs’ (FRIDs) is a common strategy to prevent falls. We conducted a systematic review to determine its efficacy for the prevention of falls and fall-related complications.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL and grey literature from inception to 1 August 2020.Eligibility criteria for selecting studiesRandomised controlled trials of FRID withdrawal compared with usual care evaluating the rate of falls, incidence of falls, fall-related injuries, fall-related fractures, fall-related hospitalisations or adverse effects related to the intervention in adults aged ≥65 years.Data extraction and synthesisTwo reviewers independently performed citation screening, data abstraction, risk of bias assessment and certainty of evidence grading. Random-effects models were used for meta-analyses.ResultsFive trials involving 1305 participants met eligibility criteria. Deprescribing FRIDs did not change the rate of falls (rate ratio (RaR) 0.98, 95% CI 0.63 to 1.51), the incidence of falls (risk difference 0.01, 95% CI −0.06 to 0.09; relative risk 1.04, 95% CI 0.86 to 1.26) or rate of fall-related injuries (RaR 0.89, 95% CI 0.57 to 1.39) over a follow-up period of 6–12 months. No trials evaluated the impact of deprescribing FRIDs on fall-related fractures or hospitalisations.ConclusionThere is a paucity of robust high-quality evidence to support or refute that a FRID deprescribing strategy alone is effective at preventing falls or fall-related injury in older adults. Although there may be other reasons to deprescribe FRIDs, our systematic review found that it may result in little to no difference in the rate or risk of falls as a sole falls reduction strategy.PROSPERO registration numberCRD42016040203.
In practice, a program may contain multiple bugs. The simultaneous presence of these bugs may deteriorate the effectiveness of existing fault-localization techniques to locate program bugs. While it ...is acceptable to use all failed and successful tests to identify suspicious code for programs with exactly one bug, it is not appropriate to use the same approach for programs with multiple bugs because the due-to relationship between failed tests and underlying bugs cannot be easily identified. One solution is to generate fault-focused clusters by grouping failed tests caused by the same bug into the same clusters. We propose MSeer-an advanced fault localization technique for locating multiple bugs in parallel. Our major contributions include the use of (1) a revised Kendall tau distance to measure the distance between two failed tests, (2) an innovative approach to simultaneously estimate the number of clusters and assign initial medoids to these clusters, and (3) an improved K-medoids clustering algorithm to better identify the due-to relationship between failed tests and their corresponding bugs. Case studies on 840 multiple-bug versions of seven programs suggest that MSeer performs better in terms of effectiveness and efficiency than two other techniques for locating multiple bugs in parallel.
The brain is thought to represent information in the form of activity in distributed groups of neurons known as attractors. We show here that in a randomly connected network of simulated spiking ...neurons, periodic stimulation of neurons with distributed phase offsets, along with standard spike-timing-dependent plasticity (STDP), efficiently creates distributed attractors. These attractors may have a consistent ordered firing pattern or become irregular, depending on the conditions. We also show that when two such attractors are stimulated in sequence, the same STDP mechanism can create a directed association between them, forming the basis of an associative network. We find that for an STDP time constant of 20 ms, the dependence of the efficiency of attractor creation on the driving frequency has a broad peak centered around 8 Hz. Upon restimulation, the attractors self-oscillate, but with an oscillation frequency that is higher than the driving frequency, ranging from 10 to 100 Hz.
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