Staphylococcus aureus, which is a leading cause of hospital-acquired infections, binds via fibronectin to integrin α5β1, a process that can promote host colonization in vivo. Integrin engagement ...induces actin cytoskeleton rearrangements that result in the uptake of S. aureus by non-professional phagocytic cells. Interestingly, we found that fibronectin-binding S. aureus trigger the redistribution of membrane microdomain components. In particular, ganglioside GM1 and GPI-linked proteins were recruited upon integrin β1 engagement, and disruption of membrane microdomains blocked bacterial internalization. Several membrane-microdomain-associated proteins, such as flotillin-1 and flotillin-2, as well as caveolin, were recruited to sites of bacterial attachment. Whereas dominant-negative versions of flotillin-2 did not affect bacterial attachment or internalization, cells deficient for caveolin-1 (Cav1(-/-)) showed increased uptake of S. aureus and other Fn-binding pathogens. Recruitment of membrane microdomains to cell-associated bacteria was unaltered in Cav1(-/-) cells. However, fluorescence recovery after photobleaching (FRAP) revealed an enhanced mobility of membrane-microdomain-associated proteins in the absence of caveolin-1. Enhanced membrane microdomain mobility and increased uptake of S. aureus was repressed by expression of wild-type caveolin-1, but not caveolin-1 G83S, which harbors a point mutation in the caveolin scaffolding domain. Similarly, chemical or physical stimulation of membrane fluidity led to increased uptake of S. aureus. These results highlight a crucial role for caveolin-1 in negative regulation of membrane microdomain mobility, thereby affecting endocytosis of bacteria-engaged integrins. This process might not only limit host cell invasion by integrin-binding bacterial pathogens, but might also be physiologically relevant for integrin-mediated cell adhesion.
Staphylococcus aureus, a Gram‐positive pathogen, invades cells mainly in an integrin‐dependent manner. As the activity or conformation of several integrin‐associated proteins can be regulated by ...phosphatidylinositol‐4,5‐bisphosphate (PI‐4,5‐P2), we investigated the roles of PI‐4,5‐P2 and PI‐4,5‐P2‐producing enzymes in cellular invasion by S. aureus. PI‐4,5‐P2 accumulated upon contact of S. aureus with the host cell, and targeting of an active PI‐4,5‐P2 phosphatase to the plasma membrane reduced bacterial invasion. Knockdown of individual phosphatidylinositol‐4‐phosphate 5‐kinases revealed that phosphatidylinositol‐4‐phosphate 5‐kinase γ (PIP5KIγ) plays an important role in bacterial internalization. Specific ablation of the talin and FAK‐binding motif in PIP5KIγ90 reduced bacterial invasion, which could be rescued by reexpression of an active, but not inactive PIP5KIγ90. Furthermore, PIP5KIγ90‐deficient cells showed normal basal PI‐4,5‐P2 levels in the plasma membrane but reduced the accumulation of PI‐4,5‐P2 and talin at sites of S. aureus attachment and overall lower levels of FAK phosphorylation. These results highlight the importance of local synthesis of PI‐4,5‐P2 by a focal adhesion‐associated lipid kinase for integrin‐mediated internalization of S. aureus.
Staphylococcus aureus can invade nonprofessional phagocytes via an FnBP‐fibronectin‐mediated linkage to host cell integrins. Shi et al. demonstrate that the integrin‐associated phosphatidylinositol‐kinase PIP5KIγ90 supports bacterial internalization via local production of phosphatidylinositol‐4,5‐bisphosphate (PIP2). Lack of PIP5KIγ90 results in diminished recruitment and activation of PIP2‐binding, integrin‐associated proteins such as talin and FAK leading to reduced host cell invasion by bacterial pathogens.
Nanobodies: COVID-19 and Future Perspectives Valenzuela-Nieto, Guillermo; Miranda-Chacon, Zaray; Salinas-Rebolledo, Constanza ...
Frontiers in drug discovery,
7/2022, Letnik:
2
Journal Article
Recenzirano
Odprti dostop
The COVID-19 pandemic has driven biotechnological developments to provide new and more effective tools for prophylaxis, diagnosis, and therapy. Historically, monoclonal antibodies have been valuable ...tools; however, the pandemic has shown some weaknesses, such as production limitations at a global scale. An alternative to conventional monoclonal antibodies are nanobodies, recombinant fragments of the variable region of single-domain antibodies derived mainly from the Camelidae family. Nanobodies have multiple characteristic benefits: they are small (15 KDa) and have remarkable refolding capability and unlimited possibilities for modifications due to their recombinant nature. Here, we review the application of nanobodies in diagnosis and treatment of SARS-CoV-2 infection.
Provider: - Institution: - Data provided by Europeana Collections- Konstanz, Universität Konstanz, Diss., 2011- All metadata published by Europeana are available free of restriction under the ...Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. ...Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6-10%, I
= 71%) while the lesion-specific clearance rate was 23% (95% CI 16-31%, I
= 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.
Recent studies have successfully demonstrated the use of deep-learning algorithms for dermatologist-level classification of suspicious lesions by the use of excessive proprietary image databases and ...limited numbers of dermatologists. For the first time, the performance of a deep-learning algorithm trained by open-source images exclusively is compared to a large number of dermatologists covering all levels within the clinical hierarchy.
We used methods from enhanced deep learning to train a convolutional neural network (CNN) with 12,378 open-source dermoscopic images. We used 100 images to compare the performance of the CNN to that of the 157 dermatologists from 12 university hospitals in Germany. Outperformance of dermatologists by the deep neural network was measured in terms of sensitivity, specificity and receiver operating characteristics.
The mean sensitivity and specificity achieved by the dermatologists with dermoscopic images was 74.1% (range 40.0%–100%) and 60% (range 21.3%–91.3%), respectively. At a mean sensitivity of 74.1%, the CNN exhibited a mean specificity of 86.5% (range 70.8%–91.3%). At a mean specificity of 60%, a mean sensitivity of 87.5% (range 80%–95%) was achieved by our algorithm. Among the dermatologists, the chief physicians showed the highest mean specificity of 69.2% at a mean sensitivity of 73.3%. With the same high specificity of 69.2%, the CNN had a mean sensitivity of 84.5%.
A CNN trained by open-source images exclusively outperformed 136 of the 157 dermatologists and all the different levels of experience (from junior to chief physicians) in terms of average specificity and sensitivity.
•A convolutional neural network (CNN) received enhanced training with 12,378 open-source dermoscopic images.•In a head-to-head comparison, the CNN outperformed 136 of 157 participating dermatologists.•The CNN was capable to outperform dermatologists of all hierarchical subgroups (from junior to chief physicians) in dermoscopic melanoma image classification.
Although there is evidence for the efficacy of internet-based cognitive behavioral therapy (iCBT), the generalizability of results to routine care is limited.
This study systematically reviews ...effectiveness studies of guided iCBT interventions for the treatment of depression or anxiety.
The acceptability (uptake, participants' characteristics, adherence, and satisfaction), effectiveness, and negative effects (deterioration) of nonrandomized pre-post designs conducted under routine care conditions were synthesized using systematic review and meta-analytic approaches.
A total of 19 studies including 30 groups were included in the analysis. Despite high heterogeneity, individual effect sizes of investigated studies indicate clinically relevant changes, with effect sizes ranging from Hedges' g=0.42-1.88, with a pooled effect of 1.78 for depression and 0.94 for anxiety studies. Uptake, participants' characteristics, adherence, and satisfaction indicate a moderate to high acceptability of the interventions. The average deterioration across studies was 2.9%.
This study provides evidence supporting the acceptability and effectiveness of guided iCBT for the treatment of depression and anxiety in routine care. Given the high heterogeneity between interventions and contexts, health care providers should select interventions that have been proven in randomized controlled clinical trials. The successful application of iCBT may be an effective way of increasing health care in multiple contexts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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