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The purpose of this study was to evaluate the pharmacokinetics of intravenous (IV) ondansetron in a population of hospitalized dogs exhibiting clinical signs of nausea. The causes of nausea included pancreatitis, gastroenteritis, endocarditis, chemotherapy-induced nausea, diabetes mellitus and ketoacidosis, acute kidney injury with aspiration pneumonia, pyometra, uroabdomen, neoplasia, and hepatopathy. Twenty-four dogs were randomly assigned to one of the following IV ondansetron protocols: 1 mg/kg q12h, 0.5 mg/kg q12h, 1 mg/kg q8h, 0.5 mg/kg q8h. Serum was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 16, and 24 h after the first dose, and nausea scores were recorded at multiple time points. Ondansetron and arginine vasopressin (AVP) concentrations were measured via high-performance liquid chromatography coupled to tandem mass spectrometry and ELISA, respectively. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Ondansetron displayed linear pharmacokinetics. In the 0.5 mg/kg group, mean C

Medical-grade masks and N95 respirators containing non-woven fibers are designed to prevent the spread of airborne diseases. While they effectively trap respiratory droplets and aerosols, they cannot lyse entrapped pathogens. Embedded antimicrobial agents such as silver, copper, zinc, iodine, peptides, quaternary ammonium salts, or nanoparticles have been used to overcome this limitation. However, their effectiveness remains debatable because these materials can be toxins, allergens, irritants, and environmental hazards. Recently, silicon nitride (Si3N4) was found to be a potent antipathogenic compound, and it may be an ideal agent for masks. In powder or solid form, it is highly effective in inactivating bacteria, fungi, and viruses while leaving mammalian tissue unaffected. The purpose of this study was to serially assess the antiviral efficacy of Si3N4 against SARS-CoV-2 using powders, solids, and embedded nonwoven fabrics. Si3N4 powders and solids were prepared using conventional ceramic processing. The “pad-dry-cure” method was used to embed Si3N4 particles into polypropylene fibers. Fabric testing was subsequently conducted using industrial standards—ISO 18184 for antiviral effectiveness, ASTM F2299 and EN 13274-7 for filtration efficiency, EN 14683 for differential pressure drop, and ISO 18562-2 for particle shedding. A modification of ISO 18562-3 was also employed to detect ammonia release from the fabric. Antiviral effectiveness for Si3N4 powders, solids, and embedded fabrics were 99.99% at ≤ 5 min, ~ 93% in 24 h, and 87% to 92% in 120 min, respectively. Results of the standard mask tests were generally within prescribed safety limits. Further process optimization may lead to commercial Si3N4-based masks that not only “catch” but also “kill” pathogenic microbes.

In addition to their role in hemostasis, platelets store numerous immunoregulatory molecules such as CD40L, TGFβ, β2-microglobulin, and IL-1β and release them upon activation. Previous studies indicate that activated platelets form transient complexes with monocytes, especially in HIV infected individuals and induce a proinflammatory monocyte phenotype. Because monocytes can act as precursors of dendritic cells (DCs) during infection/inflammation as well as for generation of DC-based vaccine therapies, we evaluated the impact of activated platelets on monocyte differentiation into DCs. We observed that in vitro cultured DCs derived from platelet-monocyte complexes (PMCs) exhibit reduced levels of molecules critical to DC function (CD206, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, CD80, CD86, CCR7) and reduced antigen uptake capacity. DCs derived from PMCs also showed reduced ability to activate naïve CD4+ and CD8+ T cells, and secrete IL-12p70 in response to CD40L stimulation, resulting in decreased ability to promote type-1 immune responses to HIV antigens. Our results indicate that formation of complexes with activated platelets can suppress the development of functional DCs from such monocytes. Disruption of PMCs in vivo via antiplatelet drugs such as Clopidogrel/Prasugrel or the application of platelet-free monocytes for DCs generation in vitro, may be used to enhance immunization and augment the immune control of HIV.

Ubiquitination is a process that acts upon every step of the HIV replication cycle. The activity, subcellular localization, and stability of HIV dependency factors as well as negative modulators can be affected by ubiquitination. These modifications consequently have an impact on the progression and outcome of infection. Additionally, recent findings suggest new roles for ubiquitination in the interplay between HIV and the cellular environment, specifically in the interactions between HIV, autophagy and apoptosis. On one hand, autophagy is a defense mechanism against HIV that promotes the degradation of the viral protein Gag, likely through ubiquitination. Gag is an essential structural protein that drives virion assembly and release. Interestingly, the ubiquitination of Gag is vital for HIV replication. Hence, this post-translational modification in Gag represents a double-edged sword: necessary for virion biogenesis, but potentially detrimental under conditions of autophagy activation. On the other hand, HIV uses Nef to circumvent autophagy-mediated restriction by promoting the ubiquitination of the autophagy inhibitor BCL2 through Parkin/PRKN. Although the Nef-promoted ubiquitination of BCL2 occurs in both the endoplasmic reticulum (ER) and mitochondria, only ER-associated ubiquitinated BCL2 arrests the progression of autophagy. Importantly, both mitochondrial BCL2 and PRKN are tightly connected to mitochondrial function and apoptosis. Hence, by enhancing the PRKN-mediated ubiquitination of BCL2 at the mitochondria, HIV might promote apoptosis. Moreover, this effect of Nef might account for HIV-associated disorders. In this article, we outline our current knowledge and provide perspectives of how ubiquitination impacts the molecular interactions between HIV, autophagy and apoptosis.

Traditional Artificial Intelligence (AI) technologies used in developing smart cities solutions, Machine Learning (ML) and recently Deep Learning (DL), rely more on utilising best representative training datasets and features engineering and less on the available domain expertise. We argue that such an approach to solution development makes the outcome of solutions less explainable, i.e., it is often not possible to explain the results of the model. There is a growing concern among policymakers in cities with this lack of explainability of AI solutions, and this is considered a major hindrance in the wider acceptability and trust in such AI-based solutions. In this work, we survey the concept of &lsquo, explainable deep learning&rsquo, as a subset of the &lsquo, explainable AI&rsquo, problem and propose a new solution using Semantic Web technologies, demonstrated with a smart cities flood monitoring application in the context of a European Commission-funded project. Monitoring of gullies and drainage in crucial geographical areas susceptible to flooding issues is an important aspect of any flood monitoring solution. Typical solutions for this problem involve the use of cameras to capture images showing the affected areas in real-time with different objects such as leaves, plastic bottles etc., and building a DL-based classifier to detect such objects and classify blockages based on the presence and coverage of these objects in the images. In this work, we uniquely propose an Explainable AI solution using DL and Semantic Web technologies to build a hybrid classifier. In this hybrid classifier, the DL component detects object presence and coverage level and semantic rules designed with close consultation with experts carry out the classification. By using the expert knowledge in the flooding context, our hybrid classifier provides the flexibility on categorising the image using objects and their coverage relationships. The experimental results demonstrated with a real-world use case showed that this hybrid approach of image classification has on average 11% improvement (F-Measure) in image classification performance compared to DL-only classifier. It also has the distinct advantage of integrating experts&rsquo, knowledge on defining the decision-making rules to represent the complex circumstances and using such knowledge to explain the results.

Platelets were recently found to harbor infectious HIV virions in infected individuals who are on antiretroviral treatment with poor CD4+ T-cell recovery. In this study, we screened platelets from recently infected individuals, before and after antiretroviral therapy, for the presence of virus and examined platelet activation, as well as CD4+ T-cell recovery. This was followed by in vitro studies assessing platelet–CD4+ T-cell complex formation as a contributing factor to viral transmission. HIV+ platelets were detected in 10 of 10 acutely infected individuals with no prior history of antiretroviral therapy. The percentage of HIV+ platelets dropped significantly after 3 months of antiretroviral therapy in all of the study participants. These individuals also demonstrated significant recovery of CD4+ T cells. Interestingly, the percentage of HIV+ platelets correlated positively with viral load but not with CD4+ T-cell count. Furthermore, we found that platelet activation with soluble CD40L or thrombin receptor activator peptide 6 (TRAP6) increased platelet-virus interactions in vitro. TRAP6-mediated interactions were reduced by platelet antagonists, aspirin, and R406. We demonstrated that platelets transmit the virus to CD4+ T cells, and this transinfection was abolished by inhibiting platelet–T-cell complex formation via exposure to an anti-CD62P antibody. Additionally, treatment with TRAP6 significantly increased the transinfection, which was also inhibited by aspirin and R206. These results reveal that platelets have the potential to promote HIV viral spread during the acute stage of infection, by harboring infectious virus transmitting infection to susceptible CD4+ T cells through complex formation.

As a potent psychosocial stressor, loneliness is associated with numerous mental and physical health complaints. The recent rise in social media use has presented opportunity for more frequent social interactions to occur with larger social networks than ever before. Somewhat paradoxically, many studies have found that increased use of social media is associated with and, may lead to, increases in loneliness and associated deleterious outcomes. However, much less is known about this relationship among homogenous populations, such as those from specific religious contexts where similar values and beliefs are shared and, in turn, may influence the interaction between the experience of loneliness and social media use. The current study addresses this research gap by exploring perceptions of loneliness (using the three-item LON measure) and daily time spent on social media (ranging from 10 min to 3 h) among 579 college students who were self-identified in the Latter-day Saint (LDS) faith at a private religious university in the Intermountain West. Those who spent more time on social media reported being lonelier, while both loneliness and time spent on social media were related to important health variables (e.g., depressive symptoms, diet, sleep, subjective health). Moreover, there appears to be two groups most at risk for experiencing greater loneliness and spending more time on social media: women, and college students not in a romantic relationship. Results are discussed in light of implications for prevention and remediation of loneliness within the college context.

Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

In recent years, deep learning has been increasingly used for several applications such as object analysis, feature extraction and image classification. This paper explores the use of deep learning in a flood monitoring application in the context of an EC-funded project, Smart Cities and Open Data REuse (SCORE). IoT sensors for detecting blocked gullies and drainages are notoriously hard to build, hence we propose a novel technique to utilise deep learning for building an IoT-enabled smart camera to address this need. In our work, we apply deep leaning to classify drain blockage images to develop an effective image classification model for different severity of blockages. Using this model, an image can be analysed and classified in number of classes depending upon the context of the image. In building such model, we explored the use of filtering in terms of segmentation as one of the approaches to increase the accuracy of classification by concentrating only into the area of interest within the image. Segmentation is applied in data pre-processing stage in our application before the training. We used crowdsourced publicly available images to train and test our model. Our model with segmentation showed an improvement in the classification accuracy.

HIV-infected individuals experience persistent inflammation, which is associated with increased platelet activation. There is growing evidence that platelets contribute to immune responses, through the release of inflammatory granules and complex formation with other cells including monocytes and CD4+ T-cells, both of which are susceptible to infection. Previous studies have found evidence that HIV is engulfed by platelets. However, such studies were primarily conducted in vitro. It is important to study consequences of HIV-platelet interactions, and to ascertain whether or not they occur in patients. We confirmed previous in vitro findings through co-culturing platelets from healthy donors, with HIV virions, and using electron microscopy identified virus-like particles inside platelets. Utilizing RNAscope in tandem with RT-PCR we created a timeline of virus-platelet associations and found viral genomic RNA remained associated with platelets for a prolonged period of time. Importantly, platelet-associated virus remained infectious, as platelets were able to spread infection to activated CD4+ T-cells in coculture experiments. Furthermore, we established a system to screen for HIV-positive platelets. We isolated platelets from cART-naïve viremic patients and performed super resolution microscopy and imagestream flow cytometry. This analysis revealed evidence of HIV-positive platelets in these infected individuals. In contrast, the amount of HIV-positive platelets was drastically, although not entirely, reduced following 3 months of cART treatment. Our findings suggest that platelet-virus interactions may be important in contributing to viral spread, and the development and maintenance of viral reservoirs.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus responsible for the development of Kaposi's sarcoma, primary effusion lymphoma (PEL), and Multicentric Castleman's disease in immunocompromised individuals. Despite the burden of these diseases there are few treatment options for afflicted individuals, due in part to our limited understanding of virus-host interactions. Tip60, a histone aceytltransferase (HAT) has been previously shown to interact with both the KSHV latency associated nuclear antigen protein (LANA), which is the main factor in maintaining the viral latent state, and ORF36, a viral kinase expressed in the lytic phase. We further investigated Tip60-virus interaction to ascertain Tip60's role in the viral life cycle and its potential as a target for future therapeutics. Through modulation of Tip60 expression in HEK293T cells harboring a plasmid containing the KSHV viral episome, Bac36, we found that Tip60 is vital for both lytic replication as well as efficient expression of latent genes. Interestingly, Tip60 small molecule inhibitors, MG149 and NU9056, similarly inhibited latent and lytic genes, and reduced virion production in wild-type KSHV+/EBV- PEL, BCBL-1 cells. Long-term treatment with these Tip60 inhibitors selectively decreased the viability of KSHV-infected B lymphoma cells compared to uninfected cells. From this study, we conclude that Tip60 is important for KSHV infection and its associated cancer development, and Tip60 is therefore a potential target for future antiviral and anticancer therapeutics.

IFI44 is an interferon-alfa inducible protein, and is associated with infection of several viruses. However, IFI44 elicits minimal antiviral effects on these viruses, and its exact role is still unknown. Here we show that IFI44 inhibits HIV-1 replication in vitro. Through depletion of endogenous IFI44 or overexpression of IFI44 we confirm that IFI44 suppresses HIV-1 LTR promoter activity and affects viral transcription. Furthermore, we find that IFI44 localizes to nuclei and binds to the HIV-1 LTR promoter in HIV-1 infected cells. Removing suppression of HIV-1 transcription benefits reactivation of HIV-1 proviruses for purging latent reservoirs. We demonstrate that depletion of endogenous IFI44 in J-LAT cells induces reactivation of latent HIV-1. Based on these results, we propose a model in which IFI44 is recruited to the HIV-1 LTR, which may suppress viral transcription and prevent reactivation of latent HIV-1. Our study suggests a previously unrecognized anti-HIV phenomenon for interferon-stimulated proteins.

While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency. BETis have emerged as a new class of compounds that are promising for this HIV-1 “shock and kill” eradication approach. However, when used as a single drug, JQ1 only modestly reverses HIV-1 latency, which complicates studying the underlining mechanisms. Meanwhile, it has been widely discussed that the induction of latent proviruses is stochastic (Ho et al., 2013). Thus, new BETis are currently under active development with focus on improving potency, ease of synthesis and structural diversity. Using fluorous-tagged multicomponent reactions, we developed a novel second-generation, 3,5-dimethylisoxazole BETi based on an imidazo[1,2-a] pyrazine scaffold, UMB-32. Furthermore, we screened 37 UMB-32 derivatives and identified that one, UMB-136, reactivates HIV-1 in multiple cell models of HIV-1 latency with better efficiency than either JQ1 or UMB-32. UMB-136 enhances HIV-1 transcription and increases viral production through the release of P-TEFb. Importantly, UMB-136 enhances the latency-reversing effects of PKC agonists (prostratin, bryostatin-1) in CD8-depleted PBMCs containing latent viral reservoirs. Our results illustrate that structurally improved BETis, such as UMB-136, may be useful as promising LRAs for HIV-1 eradication.

Nickel catalysts, supported on alumina, silica, and molybdena, have been prepared by impregnation and co-crystallization. In the precursor state the catalysts were characterised by UV–visible spectroscopy, thermogravimetric analysis/differential thermal analysis (TGA/DTA), and X-ray photoelectron spectroscopy (XPS). The nickel was principally in the 2+ oxidation state with an octahedral coordination. However, the ligand sphere surrounding the nickel ion was sensitive to the support, indicating that the species on the different supports were not identical thus suggesting a metal complex–support interaction. Reduction was followed by temperature programmed reduction (TPR) and TGA, the results of which indicated that reduction and decomposition of nickel nitrate occurred simultaneously. X-ray diffraction (XRD) analysis revealed that, with the Ni/MoO3 sample, no hydrogen bronze was formed on reduction. The reduced catalysts were characterised by carbon monoxide chemisorption, carbon dioxide chemisorption, and by reaction of buta-1,3-diene with dihydrogen. In the absence of a dihydrogen stream it was found that the catalysts adsorbed no carbon monoxide due the presence of sub-monolayer quantities of surface oxygen. The extent of the oxygen was quantified by exchange with isotopically labelled carbon dioxide. Differences in the electronic nature of the nickel between the Ni/MoO3 sample and the other catalysts wererevealedbytheirbehaviourtowardsbuta-1,3- diene hydrogenation.