The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting ...antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells.
The establishment of marine protected areas (MPAs) requires a thorough assessment of the abundance, distribution, and habitat preferences of a variety of marine species. Small cetacean spatial ...distribution and abundance were examined in the Pacific waters of Guatemala to provide this information. Boat surveys were conducted for 38 months between January 2008 and June 2012. A total of 64,678 cetaceans in 505 sightings from nine Delphinidae species were recorded. Three species, referred to as common species, accounted for 90% (
n
= 456) of all sightings. They included
Tursiops truncatus
(56%,
n
= 278),
Stenella attenuata
(29%,
n
= 143), and
Stenella longirostris
(7%,
n
= 35). Group size was significantly different among the common species (
p
< 0.001).
S. longirostris
had the largest group size (444 ± 75 dolphins), followed by
S. attenuata
(28 ± 5 dolphins), and
T
.
truncatus
(15 ± 2 dolphins).
T. truncatus
was the most common in the study area (0.02 ± 0.002 sightings/km of survey effort), and
S. attenuata
(0.37 ± 0.16 dolphins/km) and
S. longirostris
(1.62 ± 0.41 dolphins/km) were the most abundant in the neritic (≤200 m depth) and oceanic zones (≥200 m depth), respectively. The wide-ranging distribution of
T. truncatus
overlapped with the distribution of
S. attenuata
in the neritic zone and
S. longirostris
in the oceanic zone. Little overlap was observed in the distribution of
S. attenuata
and
S. longirostris
. Most hot spots (∼66%) were in the oceanic zone and no hot spots were near or in the MPAs. Hot spots were identified along the 200 m isobath, the Middle America trench, and the San José Canyon. These could be areas of high productivity where dolphins concentrate to feed. To the north of the San José Canyon, five species of small cetaceans were observed in a stretch of the neritic zone including three MPAs. No other section of this zone had such high diversity. Results need to be taken with caution given the small sample size. Our results suggest that the protection of small cetaceans needs to consider the creation of oceanic MPAs that should be integrated into the existing network.
We demonstrate that temporal characterization of ultrabroadband laser pulses (∼ 7 fs) through the d-scan technique can be implemented using ensembles of SHG micro and/or nanocrystals independently of ...their crystal size and/or composition. The experimental results have been supported by numerical simulations based on the Finite-Difference-Time-Domain (FDTD) algorithm. Both, experiment and simulations show that, in spite of the low optical quality of the samples and the unavoidable appearance of incoherent light, the technique is robust and allows to measure ultrashort laser pulses using clusters of randomly distributed and piled-up polar micro- and nanocrystals.
•Ensembles of SHG perovskite nano- and microparticles measure ultrashort pulses.•D-scan allows for temporal characterization even with partially incoherent signal.•Broadband pulse measurement is independent of crystal size and/or composition.•Simulations using FDTD-based field propagation reproduce experimental results.
Psoriasis is a chronic immune-mediated skin disease caused by several complex factors, both environmental and genetic, many of which are still not fully understood. Nowadays, several groups of ...biological drugs are being used for psoriasis treatment. Although these therapies are very effective, they show significant variability in efficacy among individuals. Therefore, there is a need for biomarkers to predict treatment outcomes in order to guide personalized therapeutic decisions. Pharmacogenetics is the study of variations in DNA sequences related to drug response.
In this article, we review pharmacogenetics studies on the treatment of moderate-to-severe psoriasis focusing on anti-interleukin (IL) 12/23 (ustekinumab) and anti-IL17 drugs (secukinumab and ixekizumab), as well as recent studies concerning anti-TNF drugs.
Several polymorphisms have been studied over the years in reference to anti-TNF drugs; some of the most recent studies included the performance of a genome-wide association study (GWAS) and pharmacogenetics studies focused on the optimization of a treatment regimen. Various polymorphisms in different genes have been related to ustekinumab response; among them, the most commonly studied is the HLA-C*06:02 allele.
Although not confirmed in some studies, most studies have shown that patients carrying this allele present a significantly higher response rate to ustekinumab. Some polymorphisms have been studied in patients treated with anti-IL17 drugs, mostly related to secukinumab; however, up to now, no association has been found between any of these polymorphisms and response. Nevertheless, further studies involving larger cohorts are needed in order to confirm these results before the implementation of this biomarker in clinical practice.
Bladder cancer (BC) is the most common neoplasia of the urothelial tract. Due to its high incidence, prevalence, recurrence and mortality, it remains an unsolved clinical and social problem. The ...treatment of BC is challenging and, although immunotherapies have revealed potential benefit in a percentage of patients, it remains mostly an incurable disease at its advanced state. Epigenetic alterations, including aberrant DNA methylation, altered chromatin remodeling and deregulated expression of non-coding RNAs are common events in BC and can be driver events in BC pathogenesis. Accordingly, these epigenetic alterations are now being used as potential biomarkers for these disorders and are being envisioned as potential therapeutic targets for the future management of BC. In this review, we summarize the recent findings in these emerging and exciting new aspects paving the way for future clinical treatment of this disease.
Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial ...data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.
5G is a key tool for the cloud-based wireless production of audio-visual contents. By providing higher throughput and lower latency than previous mobile network technologies, as well as flexible ...allocation of network resources, it enables that some content production pipelines, which are currently implemented using wired connectivity, are provided on top of a 5G network. This brings down production costs, reduces environmental impact and increases operational efficiency. In particular, live immersive production services, such as free-viewpoint video (FVV), can be provided in a much more efficient way. In this paper, we address the challenge of producing and streaming FVV services in real time through 5G networks. We have adapted a state-of-the-art FVV system to integrate it within a 5G architecture, using three key technological enablers: mmWave radio access network to support the uplink traffic requirements from FVV cameras, multi-access edge computing to run video processing algorithms with minimum latency, and end-to-end slicing to guarantee a sufficient quality of service (QoS) within the production pipeline. We have built a field trial over the production network of a telecommunication operator, including a mmWave pilot deployment, edge cloud processing, and remote content production, involving three different locations across Spain. We have measured the key performance indicators at the relevant parts of our trial deployment, showing that, with existing 5G technology, it is possible to achieve live FVV production, although with some limitations. We have also analyzed such limitations, obtaining some insights on how the next generation of 5G networks can overcome them to achieve higher quality of experience (QoE).
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances
. Recent molecular characterization has defined new (epi)genetic drivers and potential targets ...for bladder cancer
. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients
. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten
; Trp53
; Rb1
; Rbl1
) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
(1) Background: The Covid-19 pandemic has put our healthcare systems to the test, exposing their vulnerability and demanding a high degree of commitment and dedication from healthcare teams to ...confront and contain the disease. In this sense, nursing professionals have played a prominent role in the treatment of complex cases that have required hospitalisation and have manifested pre-existing health complications or mortality. This unprecedented situation made it difficult to regulate the emotional impact and manage grief, often turning it into a traumatic grief whose psychological and emotional manifestations are increasingly evident but very little researched in the current context. (2) Purpose: Validation of the definition, defining characteristics and related factors for the proposal of the nursing diagnosis of professional traumatic grief. (3) Method: Based on Fehring's content validation model, the label name, defining characteristics and other related factors were agreed upon by Spanish experts. (4) Results: The content validity index was 0.9068. A total of 21 defining characteristics were validated by the experts, as all of them scored above 0.6. With respect to the related factors of the proposed 10, all were validated. (5) Conclusion: The present study supports the proposal to develop a nursing diagnosis for professional traumatic grief. The use of standardised language is only the first step in establishing professional traumatic grief as a diagnostic category.
Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of ...standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).
Bladder cancer cell lines were tested for
sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its
activity.
Cell lines tested were sensitive to CDK4/6 inhibition, independent on
gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation
and
and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.
CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
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