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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5’-monophosphate dehydrogenase 2 (IMPDH2), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection.

Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies.

Both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) establish the persistent, life-long infection primarily at the latent status, and associate with certain types of tumors, such as B cell lymphomas, especially in immuno-compromised individuals including people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently infected viral episomes through the viral cytopathic effects and the subsequent antiviral immune responses. In this study, we identified that polo-like kinase 1 (PLK1) is induced by KSHV de novo infection as well as lytic switch from KSHV latency. We further demonstrated that PLK1 depletion or inhibition facilitates KSHV reactivation and promotes cell death of KSHV-infected lymphoma cells. Mechanistically, PLK1 regulates Myc that is critical to both maintenance of KSHV latency and support of cell survival, and preferentially affects the level of H3K27me3 inactive mark both globally and at certain loci of KSHV viral episomes. Furthremore, we recognized that PLK1 inhibition synergizes with STAT3 inhibition to efficiently induce KSHV reactivation. We also confirmed that PLK1 depletion or inhibition yields the similar effect on EBV lytic reactivation and cell death of EBV-infected lymphoma cells. Lastly, we noticed that PLK1 in B cells is elevated in the context of HIV infection and caused by HIV Nef protein to favor KSHV/EBV latency.

EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.

The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co-localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV-2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein.

Background: Malnutrition is identified as a risk-factor for insufficient polioseroconversion in the context of a vaccine-derived polio virus (VDPV) outbreak prone region. To assess the prevalence of malnutrition and its link to poliovirus insufficient immunity, a cross-sectional household survey was conducted in the regions of Haut- Lomami and Tanganyika, DRC. Methods: In March 2018, we included 968 healthy children aged 6 to 59 months from eight out of 27 districts. Selection of study locations within these districts was done using a stratified random sampling method, where villages were chosen based on habitat characteristics identified from satellite images. Consent was obtained verbally in the preferred language of the participant (French or Swahili) by interviewers who received specific training for this task. Furthermore, participants contributed a dried blood spot sample, collected via finger prick. To assess malnutrition, we measured height and weight, applying WHO criteria to determine rates of underweight, wasting, and stunting. The assessment of immunity to poliovirus types 1, 2, and 3 through the detection of neutralizing antibodies was carried out at the CDC in Atlanta, USA. Results: Of the study population, we found 24.7% underweight, 54.8% stunted, and 15.4% wasted. With IC95%, underweight (OR=1.50; [1.11– 2.03]), and the non-administration of vitamin A (OR=1.96; [1.52– 2.54]) were significantly associated with seronegativity to polioserotype 1. Underweight (OR=1.64; [1.20– 2.24]) and the non-administration of vitamin A (OR=1.55; [1.20– 2.01]) were significantly associated with seronegativity to polioserotype 2. Underweight (OR=1.50; [1.11– 2.03]), and the non-administration of vitamin A (OR=1.80. [1.38– 2.35]) were significantly associated with seronegativity to polioserotype 3. Underweight (OR=1.68; IC95% [1.10– 2.57]) and the non-administration of vitamin A (OR=1.82; IC95% [1.30– 2.55]) were significantly associated with seronegativity to all polioserotypes. Conclusion: This study reveals a significant association between underweight and polioseronegativity in children. In order to reduce vaccine failures in high-risk areas, an integrated approach by vaccination and nutrition programs should be adopted. [ABSTRACT FROM AUTHOR]

Summary: Plants are sessile and therefore have developed an extraordinary capacity to adapt to external signals. Here, the focus is on the plasticity of the plant cell to respond to new intracellular cues. Ketocarotenoids are high‐value natural red pigments with potent antioxidant activity. In the present study, system‐level analyses have revealed that the heterologous biosynthesis of ketocarotenoids in tomato initiated a series of cellular and metabolic mechanisms to cope with the formation of metabolites that are non‐endogenous to the plant. The broad multilevel changes were linked to, among others, (i) the remodelling of the plastidial membrane, where the synthesis and storage of ketocarotenoids occurs; (ii) the recruiting of core metabolic pathways for the generation of metabolite precursors and energy; and (iii) redox control. The involvement of the metabolites as regulators of cellular processes shown here reinforces their pivotal role suggested in the remodelled 'central dogma' concept. Furthermore, the role of metabolic reprogramming to ensure cellular homeostasis is proposed. [ABSTRACT FROM AUTHOR]

Doped hafnium oxide was shown to exhibit a strong ferroelectric behavior. It was implied that doping allows the stabilization of a HfO2 non-centrosymmetric orthorhombic phase, a prerequisite for ferroelectric behavior. However, a number of reports showed comparable ferroelectric properties in undoped HfO2, although with different behaviors of the remanent polarization upon layer thickness. In this work, the ferroelectric properties and crystalline structure of doped and undoped HfO2 layers as a function of the layer thickness were studied. The results show similar properties for ultrathin layers. Indeed, both show a linear increase in the orthorhombic/tetragonal crystalline phase amount and of remanent polarization as a function of thickness up to 7 nm. For higher thicknesses, a strong increase in the monoclinic phase is observed in undoped layers alongside a strong decrease in the remanent polarization whereas, for doped layers, the remanent polarization continues to increase with thickness. The experimental results suggest that the stabilization of the undoped HfO2 orthorhombic ferroelectric phase is due to mechanical stress, which is particularly high in ultrathin layers but relaxes for thicker layers. [ABSTRACT FROM AUTHOR]

Summary: Background: Contact tracing was described as a key strategy to contribute to controlling the spread of severe acute respiratory syndrome of Coronavirus 2 (SARS-CoV-2) but implementing it can be a challenge. Digitalisation of contact tracing is among the proposed solutions being explored in sub-Saharan African settings. We assessed the effectiveness of a digital tool to expand SARS-CoV-2 testing in exposed individuals in Cameroon. Methods: We conducted a cluster-randomised (1:1) trial in eight health districts, including 22 facilities and SARS-CoV-2 testing units, randomly assigned to a digital (intervention) or standard (control) contact tracing approach. The intervention consisted of a contact tracing module added to the digital platform “Mamal PRO” used for monitoring and coordination of Coronavirus Disease 2019 pandemic response in Cameroon. The primary outcome was the proportion of contacts declared by SAR-CoV-2 index patients who were successfully traced and tested for SARS-CoV-2 evaluated with a Poisson regression model with cluster adjustment. This study is registered with ClinicalTrials.gov (NCT05684887). Findings: Between October 18, 2022, and March 31, 2023, we enrolled 164 index patients in the intervention arm and 149 in the control arm, who identified 854 and 849 contacts, respectively. In the intervention arm, 93.8% (801/854) of identified contacts were successfully reached by the tracing unit versus 54.5% (463/849) in the control arm. The intervention significantly increased the likelihood of successfully tracing contacts (adjusted relative risks (RR) 1.72 [95% CI: 1.00–2.95], p = 0.049). The median (interquartile range, IQR) time to successfully tracing contacts was 0 days [IQR: 0, 1] in the intervention and 1 day [IQR: 0, 2] in the control arm. In the intervention arm, 21.3% (182/854) of identified contacts received SARS-CoV-2 testing compared to 14.5% (123/849) in the control arm (adjusted RR 1.47 [95% CI: 0.44–4.90], p = 0.530). Interpretation: Digitalising the contact tracing process improved exposure notification and facilitated the tracing of a greater number of contacts of individuals infected with SARS-CoV-2 in resource-limited settings. Funding: The study was funded by FIND, United Kingdom (FCDO 40105983), Switzerland (81066910), Netherlands (SDD 4000004160), Canada (DFATD 7429348), The Kingdom of Saudi Arabia (FIND—ACT-A DX PARTNERSHIP 20.08.2020), The Rockefeller Foundation (2020 HTH 059), Germany (BMZ Covid-19 Diagnostic and Surveillance Response 27.07.2021), Australia (DFAT 76442), Kuwait (M239/2020), The Government of Portugal and Partners (ANF, BCP, CGF, APIFARMA) and The BlackRock Foundation (Grant Agreement as of April 20, 2022).

Abstract In medical imaging, accurate segmentation is crucial to improving diagnosis, treatment, or both. However, navigating the multitude of available architectures for automatic segmentation can be overwhelming, making it challenging to determine the appropriate type of architecture and tune the most crucial parameters during dataset optimisation. To address this problem, we examined and refined seven distinct architectures for segmenting the liver, as well as liver tumours, with a restricted training collection of 60 3D contrast-enhanced magnetic resonance images (CE-MRI) from the ATLAS dataset. Included in these architectures are convolutional neural networks (CNNs), transformers, and hybrid CNN/transformer architectures. Bayesian search techniques were used for hyperparameter tuning to hasten convergence to the optimal parameter mixes while also minimising the number of trained models. It was unexpected that hybrid models, which typically exhibit superior performance on larger datasets, would exhibit comparable performance to CNNs. The optimisation of parameters contributed to better segmentations, resulting in an average increase of 1.7% and 5.0% in liver and tumour segmentation Dice coefficients, respectively. In conclusion, the findings of this study indicate that hybrid CNN/transformer architectures may serve as a practical substitute for CNNs even in small datasets. This underscores the significance of hyperparameter optimisation.

ABSTRACTThe COVID-19 booster dose is considered an important adjunct for the control of the COVID-19 pandemic due to reports of reduced immunity in fully vaccinated individuals. The aims of this study were to assess healthcare workers’ intention to receive the booster dose of COVID-19 vaccine and to identify predictive factors among healthcare workers. A cross-sectional study was conducted among healthcare workers selected in two provinces, Kasai Oriental, and Haut-Lomami. Data were collected using a questionnaire administered through structured face-to-face interviews, with respondents using a pre-tested questionnaire set up on the Open Data Kit (ODK Collect). All data were analyzed using SPSS v26.0 (IBM Corporation, Armonk, NY, USA). Vaccination coverage for COVID-19, considering declarations by health workers, is around 85.9% for the province of Kasai Oriental and 85.8% for Haut-Lomami. A total of 975 responses were collected, 71.4% of health workers at Kasai Oriental and 66.4% from Haut-Lomami declared a definite willingness to receive a COVID-19 vaccine booster. The duration of protection was the main reason for accepting a booster COVID-19 dose for 64.6% of the respondents. Logistic regression analysis showed that having chronic diseases (aOR = 2.95 [1.65–5.28]), having already received one of the COVID-19 vaccines (aOR = 2.72 [1.43–5. 19]); the belief that only high-risk individuals, such as healthcare professionals and elderly people suffering from other illnesses, needed a booster dose (aOR = 1.75 [1.10–2.81]). Considering the burden of COVID-19, a high acceptance rate for booster doses could be essential to control the pandemic. Our results are novel and could help policymakers design and implement specific COVID-19 vaccination programs to reduce reluctance to seek booster vaccination.

Sub-10 nm thick gadolinium-doped hafnia (Gd:HfO2) layers were grown in metal–insulator–metal (TiN/Gd:HfO2/TiN) stacks using a plasma-enhanced atomic layer deposition process. Thermally annealed Gd:HfO2 layers with a thickness of 8.8, 6.6, and 4.4 nm exhibited orthorhombic crystalline structure and showed ferroelectric properties. Indeed, polarization vs electric field hysteresis loops were recorded with 2Pr polarization ranging from 2 to 20 μC/cm2. The studied layers showed the same coercive electric field (∼2 MV/cm). Consequently, polarization switching voltage between +Pr and −Pr decreased down to 0.9 V for the thinnest layer. Remanent polarization cycling showed a strong wake-up effect, with no fatigue, up to 109, followed by a stabilization up to 1010 cycles, where 2Pr reached 33 μC/cm2 for 8.8 nm Gd:HfO2. This endurance result and the absence of noticeable remanent polarization fatigue can be attributed to the optimal chemical composition of the TiN/Gd:HfO2 interface, which is supposed to be at the origin of defect generation, mostly oxygen vacancies, that leads to ferroelectric polarization fatigue. [ABSTRACT FROM AUTHOR]

IntroductionThe aim of this study was to explore training and testing practices from Strength & Conditioning (S&C) coaches who manage groups of high-level French swimmers in elite training centers. The transfer of abilities from dry-land to in situ condition was also investigated.Methods24 French S&C coaches completed a survey via an online platform. Frequency analyses were made for quantitative and qualitative responses, the level of significance set for this study was p ≤ 0.05.ResultsCore stability, Strength & Power were the three most targeted qualities. Core strengthening in all its forms, Bench Press & Squat were the three most prescribed exercises. 79% of S&C coaches adapted exercises according to different parameters. Most of the coaches indicated that dry-land S&C sessions were preferentially placed before in-water sessions. Very varied exercises were used in-water to make the transfer from dry-land more effective. 87% of participants monitored the training load and 38% assessed the force and velocity parameters for some S&C exercises.DiscussionDry-land training practices of S&C coaches were mostly in line with scientific recommendations. In the light of results of the questionnaire, it would appear that testing procedures might be a key issue for transferring qualities from dry-land to in situ.