Search Results (331)

Background/Objectives: Guillain–Barré syndrome (GBS) is a neurological disease that affects the peripheral nerves. The exact cause of this condition is still uncertain, but cross-reactivity between pathogen antigens and nervous tissue may play a crucial role in disease pathogenesis. Roseolovirus humanbeta6 (HHV-6), a neurotropic virus with latency capacity, may be considered a significant candidate for triggering or worsening neurological conditions. In this study, we aimed to investigate the detection of HHV-6 in the CNS from GBS patients. Of the 23 individuals suspected of having GBS, 13 were confirmed as having the disease. We then analyzed the frequency of herpesviruses in the cerebrospinal fluid (CSF) samples from these 13 individuals with GBS who were also tested for enteroviruses and arboviruses and had negative results. Results: After extraction of viral DNA from CSF samples, real-time PCR (qPCR) methodology was used to analyze the frequency and viral load of herpesviruses. Sociodemographic and clinical data were collected for analysis and verification through statistical tests such as Fisher’s exact test and the Mann–Whitney test. Thirteen individuals diagnosed with GBS were tested. Among the 13 patients analyzed, 61.5% were men, 38.4% (5/13) tested positive for HHV-6, 61.5% of the patients tested positive for a herpesvirus, 30.8% had two viral DNAs identified, and one patient presented three different strains. Patients who tested positive for HHV-6 had a significantly longer average length of stay (25.6 days versus 11 days for negative patients). HHV-6 was the most frequent subtype detected in patients positive for herpesviruses (62.5%, 5/8). Discussion/Conclusions: Our results show a possible relationship between HHV-6 and GBS cases despite the small number of patients, raising the question of whether the presence of HHV-6 influences GBS, since its investigation using qPCR is not routinely used. This may have some impact on prognosis, since antiviral therapy is not included in the standard treatment of GBS patients, and viral DNA load may interfere with the inflammatory process of GBS. Full article

HIV-1 infection is successfully treated by antiretroviral therapy; however, it is not curative as HIV-1 remains present in the viral reservoir. A strategy to eliminate the viral reservoir relies on the reactivation of the latent provirus to subsequently trigger immune-mediated clearance. Here, we investigated whether the activation of Toll-like receptor 8 (TLR8) or RIG-I-like receptor (RLR) together with the latency reversal agent (LRA) second mitochondrial-derived activator of caspases mimetics (SMACm) leads to HIV-1 reservoir reduction and antiviral immune activation. The TLR8 and RLR agonist elicited a robust pro-inflammatory cytokine response in PBMCs from both PWH and uninfected people. Notably, co-stimulation with SMACm specifically enhanced TLR8 induced pro-inflammatory cytokine as well as CD8 T cell responses. Ex vivo treatment of PBMCs from PWH with SMACm significantly decreased the size of the inducible HIV-1 reservoir, whereas targeting TLR8 or RLR reduced the HIV-1 reservoir in 50% of PWH ex vivo. Although co-stimulation with TLR8/RLR agonists further reduced the HIV-1 reservoir in 25% of PWH ex vivo, effectively inducing antiviral immunity may help eliminate reactivated HIV-1 cells in vivo. Our findings strongly suggest that LRAs can be used in combination with agonists for pattern recognition receptors to reactivate HIV-1 and induce antiviral immunity. Full article

The “Kick and Kill” strategy, which aims to reactivate latent HIV reservoirs and facilitate the clearance of reactivated HIV-infected cells, has yet to achieve a functional cure due to the limited efficacy of current latency reversal agents. This study evaluates the combination efficacy of histone deacetylase (HDAC) inhibitor with poly(ADP-ribose) polymerase (PARP) inhibitor in latency reversal and immune-mediated clearance. Latently infected J-Lat cells and dual-fluorescent HIV-infected primary CD4 T cells were treated with the HDAC inhibitor (vorinostat) and one of four PARP inhibitors (olaparib, rucaparib, niraparib, or talazoparib). PARP inhibitors, when administered alone, showed no latency reversal activity. However, when combined with vorinostat, their efficacy increased threefold compared to vorinostat alone. This effect was mediated by the inhibition of tankyrase, a PARP superfamily member, which modulates the Hippo signaling pathway. In HIV_GR670-infected primary cells, the combination reduced the reservoir size by 67%. In addition, talazoparib alone significantly reduced actively infected cells by 50%. Talazoparib-treated peripheral blood mononuclear cells co-cultured with K562 cells demonstrated enhanced NK-cell-mediated cytotoxicity, with a 10% reduction in K562 cell viability. These findings demonstrate that combining HDAC and PARP inhibitors augments latency reversal and reservoir reduction. With both the HDAC inhibitors and PARP inhibitors used in this study approved by the FDA for cancer treatment, this combination therapy holds strong potential for rapid clinical integration, contingent upon the confirmation of efficacy and safety in ongoing in vivo studies. Full article

(1) Background: Phasic events in rapid eye movement (REM) sleep are a core feature of isolated REM behavior disorder (iRBD), which is often associated with emotion dysregulation. This study explores the relationship between sleep and the overnight habituation of emotional reactivity in healthy controls (HCs) and iRBD patients, focusing on the role of REM phasic events and a specific non-REM waveform, namely sleep spindles. (2) Methods: Participants underwent polysomnography and completed arousal rating tasks and mood scales before and after sleep. In total, eight HCs (4 M, mean age 60.62 ± 6.8) and eight iRBD patients (7 M, mean age 68.25 ± 5.12) were included in the analyses. (3) Results: In HCs, longer REM sleep duration correlated positively with overnight habituation. In the whole sample, overnight habituation negatively correlated with REM sleep latency and wake-after-sleep onset, and positively with N2 sleep. Higher overnight habituation was associated with fewer REM arousals and awakenings in the whole sample, and with greater N2 sleep spindle density in HCs. (4) Conclusions: Our preliminary results suggest that REM sleep and spindles in N2 play critical roles in emotional processing. The study confirms the relationship between emotion dysregulation and REM phasic events, enhancing our understanding of how sleep impacts emotional reactivity and also in the prodromal phase of neurodegenerative disease. Full article

HIV-1 infection cannot be cured due to the presence of HIV-1 latently infected cells. These cells do not produce the virus, but they can resume virus production at any time in the absence of antiretroviral therapy. Therefore, people living with HIV (PLWH) need to take lifelong therapy. Strategies have been coined to eradicate the viral reservoir by reactivating HIV-1 latently infected cells and subsequently killing them. Various latency reversing agents (LRAs) that can reactivate HIV-1 in vitro and ex vivo have been identified. The most potent LRAs also strongly activate T cells and therefore cannot be applied in vivo. Many LRAs that reactivate HIV in the absence of general T cell activation have been identified and have been tested in clinical trials. Although some LRAs could reduce the reservoir size in clinical trials, so far, they have failed to eradicate the reservoir. More recently, immune modulators have been applied in PLWH, and the first results seem to indicate that these may reduce the reservoir and possibly improve immunological control after therapy interruption. Potentially, combinations of LRAs and immune modulators could reduce the reservoir size, and in the future, immunological control may enable PLWH to live without developing HIV-related disease in the absence of therapy. Full article

Bovine alphaherpesvirus 1 (BoHV-1) acute infection leads to latently infected sensory neurons in trigeminal ganglia. During lytic infection, the immediate early expression of infected cell protein 0 (bICP0) and bICP4 is regulated by an immediate early transcription unit 1 (IEtu1) promoter. A separate bICP0 early (E) promoter drives bICP0 as an early viral gene, presumably to sustain high levels during productive infection. Notably, bICP0 protein expression is detected before bICP4 during reactivation from latency, suggesting the bICP0 E promoter drives bICP0 protein expression during the early phases of reactivation from latency. The glucocorticoid receptor (GR) and Krüppel-like factor 4 (KLF4) cooperatively transactivate the bICP0 E promoter despite this promoter lacks a consensus GR response element (GRE). KLF and specificity protein (Sp) family members comprise a “super-family” of transcription factors. Consequently, we hypothesized Sp1 and Sp3 transactivated the bICP0 E promoter. These studies revealed GR and Sp3 or Sp1 cooperatively transactivated bICP0 E promoter activity. KLF4 and Sp3, but not Sp1, had an additive effect on bICP0 E promoter activity. Mutating the consensus Sp1 and CACCC binding sites proximal to the TATA box impaired promoter activity more than the Sp1 sites further upstream from the TATA box. Full article

Objectives: To assess the usefulness of first amniotic sac Interleukin-6 (IL-6) to rule out intra-amniotic inflammation (IAI), as well as maternal blood c-reactive protein (CRP), to select patients with a twin pregnancy who may benefit from an emergency cerclage. Materials and Methods: Retrospective, descriptive study among all patients with a twin pregnancy and mid-trimester bulging membranes admitted to a tertiary Hospital from January 2012 to September 2023. According to the Hospital’s Protocol, all patients received a vaginal and abdominal ultrasound, a maternal blood test, and an amniocentesis of the first sac to rule out IAI, defined by IL-6 ≥ 2.6 ng/dL. Results: A total of 28 patients with a twin pregnancy and mid-trimester bulging membranes were included. Among them, 18 patients (64.28%) had IL-6 levels ≥ 2.6 ng/dL. Cerclage was placed in 10 patients with IL-6 < 2.6 ng/dL. Perinatal mortality in pregnancies with IL-6 ≥ 2.6 ng/dL was 77.22%. The gestational age at delivery of patients with IL-6 < 2.6 ng/dL was 34 ± 3 weeks, compared to 23 ± 4 weeks when IL-6 was ≥2.6 ng/dL (p < 0.001). The latency to delivery with IL-6 < 2.6 ng/dL was 88.1 ±31.56 days, compared to 13.11 ± 20.43 days when IL-6 was ≥2.6 ng/dL (p < 0.001). Significant differences were found in maternal blood CRP levels in both study groups (no IAI 4.32 ± 3.67 vs. IAI 13.32 ± 15.07, p < 0.05). The area under the curve with an ROC curve was 0.799 (IC 95% 0.596–0.929), with a cut-off of 3.9 mg/L (S 94.4%, % E 62.5%). The gestational age at delivery with CRP < 3.9 mg/L was 33 ± 5 weeks, while in cases with CRP ≥ 3.9 mg/L, it was 24 ± 5 weeks (p < 0.001). The latency days to delivery were 86.5 ± 44.88 and 21.95 ± 30.97 days (p < 0.01), respectively. A positive correlation between the IL-6 values of both amniotic sacs was obtained, along with the Spearman coefficient correlation rank (rho = 0.835, p < 0.001). Conclusions: Compared to those with IAI, patients with a twin pregnancy and mid-trimester bulging membranes without IAI who underwent emergency cerclage had a significantly higher interval from diagnosis to delivery, as well as a significantly lower incidence of preterm birth < 34 weeks and perinatal death. Further studies are needed to assess whether the IL-6 of the first amniotic sac and maternal blood CRP might constitute a useful parameter to select patients who may benefit from an emergency cerclage. Full article

Reactive astrogliosis and acidosis, common features of epileptogenic lesions, express a high level of astrocytic acid-sensing ion channel-1a (ASIC1a), a proton-gated cation channel and key mediator of responses to neuronal injury. This study investigates the role of astrocytic ASIC1a in cognitive impairment following epilepsy. Status epilepticus (SE) in C57/BL6 mice was induced using lithium–pilocarpine; the impact of ASIC1a on astrocytes was assessed using rAAV–ASIC1a–NC and rAAV–ASIC1a–shRNA, injected in the CA3 region of mice. Behavioral assessments were conducted using the Morris water maze (MWM). Western blotting and immunofluorescence were applied to evaluate ASIC1a and Gfap expression while analyzing intracellular calcium and extracellular glutamate (Glu) concentrations in primary cultured astrocytes isolated from the brains of 1 to 3-day-old mice and treated LPS. Results showed enhanced astrocyte proliferation and ASIC1a expression in the dentate gyrus of epileptic mice 7, 21, and 28 days post-SE (all p < 0.05). Escape latency in the MWM further suggested that ASIC1a regulates cognitive function in mice with chronic epilepsy. LPS stimulation in vitro mimicked inflammatory responses, increasing ASIC1a after 24 h, which increased the concentration of intracellular calcium and extracellular expression of Glu; inhibition of ASIC1a expression reversed this process. To sum up, these data confirm that astrocytic ASIC1a may facilitate cognitive dysfunction post-epilepsy, presenting a potential therapeutic target. Full article

Pityriasis rosea (PR) is a self-limited exanthem associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and HHV-7. The disease typically begins with a single erythematous patch on the trunk (herald patch), followed by a secondary eruption of smaller papulosquamous lesions. Rarely, the herald patch may be the only cutaneous manifestation of PR. The present work aimed to examine the clinical and laboratory features of the PR cases characterized by the herald patch as the sole cutaneous manifestation and to compare them with the classic form of PR. An observational, retrospective study was conducted on patients presenting with herald patch as the only sign of PR (cases) and on a series of age- and sex-matched patients who presented with a typical PR pattern (controls). The records of the patients were extracted from a PR registry, which collected data on patients with PR diagnosed from 2003 to 2023 by at least two dermatologists from the same study team. Nineteen patients (eleven males, eight females) with a mean age of 27.1 years presented the herald patch as the only cutaneous manifestation of PR. Nineteen age- and sex-matched patients were considered controls. In the cases, the exanthem duration was shorter than in controls, and the mean HHV-6 and HHV-7 DNA plasma load was lower than in controls. This rare variant of PR might be considered an abortive form of the exanthem that occurs when the HHV-6/7 reactivation from latency is contrasted by a more robust immunological response than in classic PR. Full article

Background: Human immunodeficiency virus (HIV) establishes latent infections in cellular reservoirs, including microglia. HC69 cells, a microglial model of HIV latency, contain an HIV promoter long terminal repeat (LTR)-GFP reporter and were used for testing the efficacy of a two-step magnetoelectric nanoparticle (MENP) and extracellular vesicle (xEV) latency-targeting (MELT) nanotherapeutic. GFP expression in HC69 at rest is low (GFP^Lo), and upon exposure to LTR, transcription-activating agents (i.e., TNF-α) are induced to be high expressing (GFP^Hi). Methods: The first step of MELT utilized ZL0580, an HIV Tat inhibitor loaded into EVs (80%) via incubation. ZL0580-EVs were taken up by GFP^Lo and blocked LTR transcriptional reactivation by 50% and were 90% less toxic than ZL0580 alone. The second step in MELT involved conjugation of monomethyl auristatin E (MMAE) to MENPs. HPLC measurements showed 80% MMAE attachment to MENPs. Flow cytometry-based measurements of the membrane potential indicated that the membranes of GFP^Hi HC69 were 60% more polarized than GFP^Lo HC69 cells. More MMAE–MENPs were internalized by GFP^Lo HC69. Results: Using a mixed-cell blood–brain barrier (BBB) Transwell model, we demonstrated that 20% of MELT crossed the BBB, was taken up by HC69 cells, and reduced LTR reactivation by 10%. Conclusions: Overall, this study demonstrated that MELT can potentially be utilized as a nanotherapeutic to target HIV latency in microglia. Full article

Herpesviruses are a group of DNA viruses capable of infecting multiple mammalian species, including humans. This review primarily summarizes four common alphaherpesviruses found in pets and livestock (feline, swine, canine, and bovine) in aspects such as epidemiology, immune evasion, and latency and reactivation. Despite the fact that they primarily infect specific hosts, these viruses have the potential for cross-species transmission due to genetic mutations and/or recombination events. During infection, herpesviruses not only stimulate innate immune responses in host cells but also interfere with signaling pathways through specific proteins to achieve immune evasion. These viruses can remain latent within the host for extended periods and reactivate under certain conditions to trigger disease recurrence. They not only affect the health of animals and cause economic losses but may also pose a potential threat to humans under certain circumstances. This review deepens our understanding of the biological characteristics of these animal alphaherpesviruses and provides an important scientific basis for the prevention and control of related diseases. Full article

RNA-binding proteins (RBPs) are cellular factors involved in every step of RNA metabolism. During HIV-1 infection, these proteins are key players in the fine-tuning of viral and host cellular and molecular pathways, including (but not limited to) viral entry, transcription, splicing, RNA modification, translation, decay, assembly, and packaging, as well as the modulation of the antiviral response. Targeted studies have been of paramount importance in identifying and understanding the role of RNA-binding proteins that bind to HIV-1 RNAs. However, novel approaches aimed at identifying all the proteins bound to specific RNAs (RBPome), such as RNA interactome capture, have also contributed to expanding our understanding of the HIV-1 replication cycle, allowing the identification of RBPs with functions not only in viral RNA metabolism but also in cellular metabolism. Strikingly, several of the RBPs found through interactome capture are not canonical RBPs, meaning that they do not have conventional RNA-binding domains and are therefore not readily predicted as being RBPs. Further studies on the different cellular targets of HIV-1, such as subtypes of T cells or myeloid cells, or on the context (active replication versus reactivation from latency) are needed to fully elucidate the host RBPome bound to the viral RNA, which will allow researchers and clinicians to discover new therapeutic targets during active replication and provirus reactivation from latency. Full article

In mission-critical environments such as industrial and military settings, the use of unmanned vehicles is on the rise. These scenarios typically involve a ground control system (GCS) and nodes such as unmanned ground vehicles (UGVs) and unmanned aerial vehicles (UAVs). The GCS and nodes exchange different types of information, including control data that direct unmanned vehicle movements and sensor data that capture real-world environmental conditions. The GCS and nodes communicate wirelessly, leading to loss or delays in control and sensor data. Minimizing these issues is crucial to ensure nodes operate as intended over wireless links. In dynamic networks, distributed path calculation methods lead to increased network traffic, as each node independently exchanges control messages to discover new routes. This heightened traffic results in internal interference, causing communication delays and data loss. In contrast, software-defined networking (SDN) offers a centralized approach by calculating paths for all nodes from a single point, reducing network traffic. However, shifting from a distributed to a centralized approach with SDN does not inherently guarantee faster route creation. The speed of generating new routes remains independent of whether the approach is centralized, so SDN does not always lead to faster results. Therefore, a key challenge remains: determining how to create new routes as quickly as possible even within an SDN framework. This paper introduces a caching technique for forwarding rules based on predicted link states in SDN, which was named the CRIMSON (Cashing Routing Information in Mobile SDN Network) algorithm. The CRIMSON algorithm detects network link state changes caused by node mobility and caches new forwarding rules based on predicted topology changes. We validated that the CRIMSON algorithm consistently reduces end-to-end latency by an average of 88.96% and 59.49% compared to conventional reactive and proactive modes, respectively. Full article

Amphetamine abuse is a global health epidemic that is difficult to treat due to individual differences in response to environmental factors, including stress reactivity and anxiety levels, as well as individual neuronal differences, which may result in increased/decreased vulnerability to addiction. In the present study, we investigated whether the Wistar rats behavioral traits of high (HR) and low (LR) locomotor activity to novelty influence motivational behavior (induced feeding model; iFR by electrical stimulation of the ventral tegmental area; Es-VTA) supported by amphetamine injection into the nucleus accumbens shell (AcbSh) (HR_Amph, n = 5; LR_Amph, n = 5). A correlation was found between the novelty test’s locomotor activity score and the frequency threshold percentage change (p < 0.001, Rs = −0.867). In HR_Amph, there was a shortening (−24.16%), while in LR_Amph, there was a lengthening (+51.84%) of iFR latency. Immunofluorescence studies showed differential neuronal density (activity of tyrosine hydroxylase, choline acetyltransferase, and cFos protein) in the selected brain structures in HR_Amph and LR_Amph animals as well as in comparison to a control group (HR_ACSF, n = 5; LR_ACSF, n = 5). These results contribute to expanding the state of knowledge of the behavioral and neuronal propensity to take drug abuse. Full article

Modern software application development imposes standards regarding high performance, scalability, and minimal system latency. Multi-threading asynchronous programming is one of the standard solutions proposed by the industry for achieving such objectives. However, the recent introduction of the reactive programming interface in Java presents a potential alternative approach for addressing such challenges, promising performance improvements while minimizing resource utilization. The research examines the migration process from the asynchronous paradigm to the reactive paradigm, highlighting the implications, benefits, and challenges resulting from this transition. To this end, the architecture, technologies, and design of a support application are presented, outlining the practical aspects of this experimental process while closely monitoring the phased migration. The results are examined in terms of functional equivalence, testing, and comparative analysis of response times, resource utilization, and throughput, as well as the cases where the reactive paradigm proves to be a solution worth considering. Across multiple scenarios, the reactive paradigm demonstrated advantages such as up to 12% reduction in memory usage, 56% faster 90th percentile response times, and a 33% increase in throughput under high-concurrency conditions. However, the results also reveal cases, such as data-intensive scenarios, where asynchronous programming outperforms reactive approaches. Additionally, possible directions for further research and development are presented. This paper not only investigates the design and implementation process but also sets a foundation for future research and innovation in dependable systems, collaborative technologies, sustainable solutions, and distributed system architecture. Full article