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Rift Valley Fever Virus (RVFV) is an arbovirus that predominantly affects sheep, goats, and cattle, causing epizootics in livestock and epidemics in humans. Infection in pregnant livestock leads to high abortion rates and neonatal mortality. In humans, RVFV usually causes a self-limiting febrile illness, but severe forms can develop, such as hepatitis, hemorrhage, encephalitis, and death. In addition, the association between RVFV infection during pregnancy and miscarriages or stillbirths has been documented. RVFV is transmitted by a range of mosquito species, and, due to the diffusion of these insects, the virus has spread in several world regions, making possible the risk of a public health emergency. Nevertheless, research remains limited and cellular pathology is still poorly characterized. This work aimed to fill some knowledge gaps on the comprehension of RVFV pathogenesis. For this purpose, transmission electron microscopy (TEM) was used to analyze cellular modifications associated with RVFV morphogenesis in four human cell lines (HuH-7, LAN-5, A549, and HTR-8/SVneo) derived from liver, brain, lung, and placenta. Our results showed that all four cell lines are permissive to RVFV infection and highlighted differences in the cytopathogenesis associated with the cell type. These findings could have important implications in understanding disease mechanisms and developing antiviral strategies.

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide and is mostly caused by hepatitis B virus (HBV) infection. HBV can induce HCC by an indirect mechanism of continuous necro-inflammation, contributing to hepatocyte damage and promoting cancer, as well as by viral intrinsic factors. Among them, the major contributors to the development of HBV-related HCC are represented by (i) HBV DNA integration in genes modulating cell proliferation, (ii) HBV pro-oncogenic proteins, such as HBx and HBs, and (iii) the accumulation of viral mutations, enhancing the tumorigenic features of HBV proteins. The currently available antiviral treatments, based on the usage of Nucleos(t)ide analogs (NUCs), substantially control HBV replication. However, even a successful NUC treatment does not completely abrogate HCC risk, since it rarely allows achievement of an HBV functional cure, the therapeutic end-point associated with HBsAg loss and more favorable liver outcomes. To date, novel therapeutic strategies based on innovative direct antivirals (nucleic acid polymers, small interfering RNAs, antisense oligonucleotides, covalently closed circular DNA (cccDNA) inhibitors, and capsid assembly modulators) and immune-therapeutics (therapeutic vaccines, checkpoint inhibitors, and Toll-like receptor agonists) are under evaluation in clinical trials. These approaches are showing promising data in terms of an HBV functional cure, thus representing novel strategies that could be beneficial for reducing the burden of HBV-related HCC. Lastly, further efforts in drug development are necessary to identify new compounds that could achieve a sterilizing HBV cure, implying the complete elimination of cccDNA and integrated HBV DNA, the only end-point that completely eradicates HBV and its related oncogenic risk.

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.

In this study, we provided a retrospective overview in order to better define SARS-CoV-2 variants circulating in Italy during the first two years of the pandemic, by characterizing the spike mutational profiles and their association with viral load (expressed as ct values), N-glycosylation pattern, hospitalization and vaccination. Next-generation sequencing (NGS) data were obtained from 607 individuals (among them, 298 vaccinated and/or 199 hospitalized). Different rates of hospitalization were observed over time and among variants of concern (VOCs), both in the overall population and in vaccinated individuals (Alpha: 40.7% and 31.3%, Beta: 0%, Gamma: 36.5% and 44.4%, Delta: 37.8% and 40.2% and Omicron: 11.2% and 7.1%, respectively, both p-values < 0.001). Approximately 32% of VOC-infected individuals showed at least one atypical major spike mutation (intra-prevalence > 90%), with a distribution differing among the strains (22.9% in Alpha, 14.3% in Beta, 41.8% in Gamma, 46.5% in Delta and 15.4% in Omicron, p-value < 0.001). Overall, significantly less atypical variability was observed in vaccinated individuals than unvaccinated individuals; nevertheless, vaccinated people who needed hospitalization showed an increase in atypical variability compared to vaccinated people that did not need hospitalization. Only 5/607 samples showed a different putative N-glycosylation pattern, four within the Delta VOC and one within the Omicron BA.2.52 sublineage. Interestingly, atypical minor mutations (intra-prevalence < 20%) were associated with higher Ct values and a longer duration of infection. Our study reports updated information on the temporal circulation of SARS-CoV-2 variants circulating in Central Italy and their association with hospitalization and vaccination. The results underline how SARS-CoV-2 has changed over time and how the vaccination strategy has contributed to reducing severity and hospitalization for this infection in Italy.

A strategy adopted to combat human immunodeficiency virus type-1 (HIV-1) infection is based on interfering with virus entry into target cells. In this study, we found that phosphatidylcholine (PC) liposomes reduced the expression of the CD4 receptor in human primary type-1 macrophages but not in CD4 + T cells. The down-regulation was specific to CD4, as any effect was not observed in CCR5 membrane expression. Moreover, the reduction of membrane CD4 expression required the Ca 2+ -independent protein kinase C (PKC), which in turn mediated serine phosphorylation in the intracytoplasmic tail of the CD4 receptor. Serine phosphorylation of CD4 was also associated with its internalization and degradation in acidic compartments. Finally, the observed CD4 downregulation induced by PC liposomes in human primary macrophages reduced the entry of both single-cycle replication and replication competent R5 tropic HIV-1. Altogether, these results show that PC liposomes reduce HIV entry in human macrophages and may impact HIV pathogenesis by lowering the viral reservoir.

Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico. HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D(N = 228), -A(N = 65) and -E(N = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7-3.8]IU/ml; 3.8[3.5-4.2]IU/ml and 3.9[3.7-4.2]IU/ml, P < 0.001). Results confirmed by multivariable analysis correcting for patients'demographics, HBV-DNA, ALT and infection-status. In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg<1000IU/ml(P-value from <0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A + F220L (Phi = 0.41, P = 0.003), S204N + L205P (Phi = 0.36, P = 0.005), Y206F + S210R (Phi = 0.47, P < 0.001) and S210N + F220L (Phi = 0.40, P = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them(P-value from 0.003 to 0.02). In-vitro, the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt(P-value from <0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain. In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo, hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.

A bstract We provide a complete and detailed study of the high-energy limit of four-parton scattering amplitudes in QCD, giving explicit results at two loops and higher orders, and going beyond next-to-leading logarithmic (NLL) accuracy. Building upon recent results, we use the techniques of infrared factorization to investigate the failure of the simplest form of Regge factorization, starting at next-to-next-to-leading logarithmic accuracy (NNLL) in ln( s/ | t |). We provide detailed accounts and explicit expressions for the terms responsible for this breaking in the case of two-loop and three-loop quark and gluon amplitudes in QCD; in particular, we recover and explain a known non-logarithmic double-pole contribution at two-loops, and we compute all non-factorizing single-logarithmic singular contributions at three loops. Conversely, we use high-energy factorization to show that the hard functions of infrared factorization vanish in d = 4 to all orders in the coupling, up to NLL accuracy in ln( s/ | t |). This provides clear evidence for the infrared origin of high-energy logarithms. Finally, we extend earlier studies to t -channel exchanges of color representations beyond the octet, which enables us to give predictions based on the dipole formula for single-pole NLL contributions at three and four loops.

Territorial systems of Neotropical birds remain poorly understood, especially considering the effect of interspecific interactions. Studies on territorial behavior provide information about demography and life history, and are useful for the refinement of conservation strategies. We assessed territories of six species of antbirds (Thamnophilidae) from August 2010 to May 2011 at Pedra Azul State Park, a protected area in southeastern Brazil, in a 30-ha sampling grid. Birds were captured, marked, and followed through the study area. Territory sizes of Plain Antvireo (Dysithamnus mentalis), Ferruginous Antbird (Drymophila ferruginea), Ochre-rumped Antbird (Drymophila ochropyga), White-bibbed Antbird (Myrmeciza loricata), White-shouldered Fire-eye (Pyriglena leucoptera), and Variable Antshrike (Thamnophilus caerulescens) were estimated by the convex polygon method. We found 46 territories of the six species. We compared and evaluated the effect of body size on territories among the species. Males and females were active in territory defense by emitting songs and calls. The mean territory sizes defended by the six species varied from 0.72–1.18 ha. We found empty spaces between territories and a high overlap rate among territories of different species, but no overlap within species. Thamnophilus caerulescens had the highest density and D. mentalis and D. ferruginea had lower densities. Body mass and distance to the forest edge had no effect on territory size. The territory assessment provided a precise density estimation of individuals in the study area.

The identification of predators of birds' nests, crucial to a better understanding of predator-prey interactions, remains poorly known. Here we provide evidence that birds, and especially passerines, may depredate birds' nests in the Cerrado (Neotropical Savannah) of Central Brazil. Data was collected primarily in a Conservation Unit (Estação Ecológica de _guas Emendadas) during the breeding season, between 2003 and 2007. We report and discuss details on 14 events of nest predation, 12 of which by passerines, mostly by curl-crested jays - Cyanocorax cristatellus (Temminck, 1823). The results of our study suggest that the role of birds as nest predators in the Cerrado has been underestimated and needs to be further investigated.

Magistrates of the Supreme Court of Justice, the Constitutional Court, the specialized high Agro-Environmental Court, and the Magistrates' Council (supervisory and administrative body of the judicial branch) are now elected by vote of all of the population of age, based on a list of candidates preselected by Congress.2 The first such election took place on October 16, 2011, after a heated controversy between partisans of President Evo Morales and opposition and civic groups that criticized the pre-selection congressional procedure as favoring candidates that supported President Morales's polities, and therefore lacking the independence needed for the exercise of judicial functions.