Search Results (97)

Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer’s disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS. Full article

Vpr, a virion-associated accessory virulence factor of HIV-1, promotes virus replication in both T cells and macrophages. Although Vpr’s early activity—antagonism of preintegration silencing and host restriction factors—has been documented, the relative contribution of virion-associated versus de novo expressed Vpr to HIV-1 replication fitness remains unclear. Here, we developed a T cell-based system that genetically separates early and late Vpr functions by combining tetracycline-inducible Vpr expression in CEM.SS T cells with vpr-deficient HIV-1 constructs and Gag p6 mutations that block Vpr packaging. CEM.SS T cells have been shown to recapitulate the positive effect of Vpr on HIV-1 replication observed in activated primary T cells. Using pairwise replication fitness assays under spreading infection conditions, we demonstrate that de novo synthesized Vpr exerts the dominant effect on HIV-1 replication in T cells, while virion-associated Vpr plays a lesser role. Somewhat unexpectedly, our findings reveal that antagonism of preintegration HIV-1 silencing by virion-associated Vpr is unlikely to be the major driver of enhanced HIV-1 replication in proliferating T cells. Instead, this function may play a more prominent role in the infection of non-dividing T cells and/or other cell types. Full article

Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy and presents as gradual visual loss caused by the loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a mitochondrial GTPase essential in mitochondrial fusion. Currently, there are no treatments for DOA. Here, we tested the therapeutic potential of an approach to DOA using CRISPR activation (CRISPRa). Homology directed repair was used to introduce a common OPA1 pathogenic variant (c.2708_2711TTAGdel) into HEK293T cells as an in vitro model of DOA. Heterozygous c.2708_2711TTAGdel cells had reduced levels of OPA1 mRNA transcript, OPA1 protein, and mitochondrial network alterations. The effect of inactivated Cas9 fused to an activator (dCas9–VPR) was tested with a range of guide RNAs (gRNA) targeted to the promotor region of OPA1. gRNA3 and dCas9–VPR increased OPA1 expression at the RNA and protein level towards control levels. Importantly, the correct ratio of OPA1 isoform transcripts was maintained by CRISPRa. CRISPRa-treated cells showed an improvement in mitochondrial networks compared to untreated cells, indicating partial rescue of a disease-associated phenotype. Collectively, these data support the potential application of CRISPRa as a therapeutic intervention in DOA. Full article

Background: Cancer vaccines represent a groundbreaking advancement in cancer immunotherapy, utilizing tumor antigens to induce tumor-specific immune responses. However, challenges like tumor-induced immune resistance and technical barriers limit the widespread application of predefined antigen vaccines. Here, we investigated the potential of viral protein R (Vpr) peptides as effective candidates for constructing anonymous antigen vaccines in situ by directly injecting at the tumor site and releasing whole-tumor antigens, inducing robust anti-tumor immune responses to overcome the limitations of predefined antigen vaccines. Methods: The cytotoxic effects of Vpr peptides were evaluated using the CCK8 reagent kit. Membrane penetration ability of Vpr peptides was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. EGFR levels in the cell culture supernatants of cells treated with Vpr peptides were evaluated using an ELISA. Surface exposure of CRT on the tumor cell surface was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. The secretion levels of ATP from tumor cells were evaluated using an ATP assay kit. HMGB1 release was evaluated using an ELISA. Mouse (Male C57BL/6 mice aged 4 weeks) MC38 and LLC bilateral subcutaneous tumor models were established to evaluate the therapeutic effects of Vpr peptides through in situ vaccination. Proteomic analysis was performed to explore the mechanism of anti-tumor activity of Vpr peptides. Results: Four Vpr peptides were designed and synthesized, with P1 and P4 exhibiting cytotoxic effects on tumor cells, inducing apoptosis and immunogenic cell death. In mouse tumor models, in situ vaccination with Vpr peptide significantly inhibited tumor growth and activated various immune cells. High-dose P1 monotherapy demonstrated potent anti-tumor effects, activating DCs, T cells, and macrophages. Combining ISV of P1 with a CD47 inhibitor SIRPαFc fusion protein showed potent distant tumor suppression effects. Proteomic analysis suggested that Vpr peptides exerted anti-tumor effects by disrupting tumor cell morphology, movement, and adhesion, and promoting immune cell infiltration. Conclusions: The designed Vpr peptides show promise as candidates for in situ vaccination, with significant anti-tumor effects, immune activation, and favorable safety profiles observed in mouse models. In situ vaccination with Vpr-derived peptides represents a potential approach for cancer immunotherapy. Full article

Visual Place Recognition (VPR) constitutes a pivotal task in the domains of computer vision and robotics. Prevailing VPR methods predominantly employ RGB-based features for query image retrieval and correspondence establishment. Nevertheless, such unimodal visual representations exhibit inherent susceptibility to environmental variations, inevitably degrading method precision. To address this problem, we propose a robust VPR framework integrating RGB and depth modalities. The architecture employs a coarse-to-fine paradigm, where global retrieval of top-N candidate images is performed using fused multimodal features, followed by a geometric verification of these candidates leveraging depth information. A Discrete Wavelet Transform Fusion (DWTF) module is proposed to generate robust multimodal global descriptors by effectively combining RGB and depth data using discrete wavelet transform. Furthermore, we introduce a Spiking Neuron Graph Matching (SNGM) module, which extracts geometric structure and spatial distance from depth data and employs graph matching for accurate depth feature correspondence. Extensive experiments on several VPR benchmarks demonstrate that our method achieves state-of-the-art performance while maintaining the best accuracy–efficiency trade-off. Full article

Aiming at the problem of appearance drift and susceptibility to noise interference in visual place recognition (VPR), we propose DD–DPFE: a Dynamic Difference and Dual-Path Feature Enhancement method. Embedding differential attention mechanisms in the DINOv2 model to mitigate the effects of process interference and adding serial-parallel adapters allows efficient model parameter migration and task adaptation. Our method constructs a two-way feature enhancement module with global–local branching synergy. The global branch employs a dynamic fusion mechanism with a multi-layer Transformer encoder to strengthen the structured spatial representation to cope with appearance changes, while the local branch suppresses the over-response of redundant noise through an adaptive weighting mechanism and fuses the contextual information from the multi-scale feature aggregation module to enhance the robustness of the scene. The experimental results show that the model architecture proposed in this paper is an obvious improvement in different environmental tests. This is most obvious in the simulation test of a night scene, verifying that the proposed method can effectively enhance the discriminative power of the system and its anti-jamming ability in complex scenes. Full article

HIV, primarily targeting CD4 cells, infiltrates the CNS through various mechanisms, including chemokine-mediated signaling and blood–brain barrier disruption, leading to neuroinflammation and neuronal dysfunction. Viral proteins such as gp120, Tat, and Vpr directly induce neurotoxicity, oxidative stress, and mitochondrial dysfunction, exacerbating cognitive deficits and motor impairments observed in HIV-associated neurocognitive disorders (HANDs). Host genetic factors, including CCR5 mutations and HLA alleles, influence susceptibility to HIV-related neurologic complications, shaping disease progression and treatment responses. Advanced molecular and bioinformatics techniques, from genome sequencing to structural modeling and network analysis, provide insights into viral pathogenesis and identify potential therapeutic targets. These findings underscore the future potential of precision medicine approaches tailored to individual genetic profiles to mitigate neurologic complications and improve outcomes in HIV-infected populations. This comprehensive review explores the intricate interplay between HIV infection and neurogenetics, focusing on how the virus impacts the central nervous system (CNS) and contributes to neurocognitive disorders. This report delves into how the virus influences genetic expression, neuroinflammation, and neurodegeneration, offering insights into molecular mechanisms behind HAND. Full article

This study presents a comprehensive dosimetric characterization and commissioning of a grid-type collimator manufactured via 3D printing using PLA-W composite filament, following an international protocol for small-field dosimetry. PLA doped with high concentrations of tungsten (>90% w/w) enables the fabrication of miniaturized collimators (<1 cm) with complex geometries, suitable for non-conventional radiotherapy applications. However, accurate assessment of spatial dose modulation is challenged by penumbra overlap between closely spaced beamlets, limiting the application of conventional instrumentation and protocols. To address this, absolute and relative dose distributions were evaluated for various radiation field configurations (number of beamlets) in both lateral and depth directions. Measurements were performed according to the IAEA TRS-483 protocol, using micro-ionization chambers and diode detectors. Additionally, long-term stability assessments were carried out to evaluate both the structural integrity and modulation performance of the printed grid over time. Point dose measurements using the same detectors were repeated after one year, and 2D surface dose distributions measured with EBT3 films were compared to SRS MapCHECK measurements two years later. The generated radiation field size of the central beamlet (FWHM) differed by less than 0.2% (15.8 mm) from the physical projection size (15.6 mm) and the lateral transmission due simultaneous beamlets resulted in FWHM variations of less than 3.8%, confirming manufacturing precision and collimator capability. Output factor measurements increased with the number of beamlets, from 0.75 for a single beamlet to 0.82 for the full beamlets configuration. No significant changes were observed in the depth of maximum dose across the different beamlets configurations (1.20 ± 0.20 cm). On the other hand, the long-term evaluations show no relevant changes in the FWHM or VPR, confirming the performance and reliability of the system. These results support the clinical feasibility and lasting performance stability of in-house manufactured grid collimators using PLA-W filaments and accessible 3D printing technology. Full article

The human immunodeficiency virus (HIV-1) infiltrates the central nervous system (CNS) early in infection, leading to HIV-associated neurocognitive impairments, particularly pronounced in children who exhibit neurodevelopmental delay. Viral proteins, including the transactivator of transcription protein (Tat) and viral protein R (Vpr) are pivotal in HIV-1 neuropathogenesis, with their amino acid sequence variation influencing disease progression. Due to the difficulty of collecting cerebrospinal fluid from children, few studies have examined whether key Tat and Vpr neuropathogenic signatures found in blood are also present in the cerebrospinal fluid (CSF) of children with HIV. We employed Sanger sequencing for Tat and Vpr sequence analysis using retrospectively collected CSF samples from a South African pediatric HIV-1 subtype C cohort (n = 4). We compared our CSF-derived sequences with pediatric blood-derived sequences (n = 43) from various geographical regions, sourced from the Los Alamos database. Neuropathogenic amino acid variants were identified in Tat and Vpr sequences derived from CSF samples of South African pediatric participants No significant differences were found between subtype C sequences from CSF and blood. Regional analysis highlighted unique amino acid signatures. Obtaining pediatric CSF for HIV-1 sequencing is highly challenging. Despite a small sample size, this study offers rare insights into Tat and Vpr sequences in children, improving understanding of the potential HIV-1 brain pathogenesis in pediatric populations. Full article

This review explores the mechanisms by which Human Immunodeficiency Virus type 1 (HIV-1) regulatory proteins manipulate host cellular pathways to promote viral replication and immune evasion. Key viral proteins, such as Nef, Vpu, Vif, Vpr, and Env, disrupt immune defenses by downregulating surface molecules such as CD4 (Cluster of Differentiation 4) and Major Histocompatibility Complex (MHC) class I, degrading antiviral enzymes like APOBEC3G (Apolipoprotein B mRNA editing catalytic polypeptide-3G) and SAMHD1 (Sterile Alpha Motif and Histidine Aspartate domain-containing protein 1), and counteracting restriction factors including BST-2 (Bone Marrow Stromal Antigen 2)/Tetherin and SERINC5 (Serin Incorporator 5). These interactions support viral persistence and contribute to the establishment of chronic infection. Emerging therapeutic strategies aim to disrupt these HIV-host interactions to restore innate antiviral responses and enhance immune clearance. Approaches such as stabilizing host restriction factors or blocking viral antagonists offer a promising alternative to conventional antiretroviral therapy. By targeting host-dependent pathways, these interventions may reduce drug resistance, tackle latent reservoirs, and provide a pathway toward sustained viral remission or functional cure. Full article

Visual place recognition (VPR) is crucial for enabling autonomous agents to accurately localize themselves within a known environment. While existing methods leverage neural networks to enhance performance and robustness, they often suffer from the limited representation power of local feature extractors. To address this limitation, we propose CriSALAD, a novel VPR model that integrates visual foundation models (VFMs) and cross-image information to improve feature extraction robustness. Specifically, we adapt pre-trained VFMs for VPR by incorporating a parameter-efficient adapter inspired by Xception, ensuring effective task adaptation while preserving computational efficiency. Additionally, we employ the Sinkhorn Algorithm for Locally Aggregated Descriptors (SALAD) as a global descriptor to enhance place recognition accuracy. Furthermore, we introduce a transformer-like cross-image encoder that facilitates information sharing between neighboring images, thus enhancing feature representations. We evaluate CriSALAD on multiple publicly available place recognition datasets, achieving promising performance with a recall@1 of 89.3% on the Nordland dataset, while the closest rival achieves only 76.2%. CriSALAD outperforms both baseline models and advanced VFM-based VPR approaches. Full article

In this work, YF₃:Nd³⁺ powder was synthesized using the microwave-assisted hydrothermal method at a low temperature (140 °C) and short synthesis time (1 h). The photoluminescence and optical temperature sensing properties of YF₃:Nd³⁺ were examined using 800 nm laser excitation, focusing on the emission corresponding to the ⁴F_3/2 → ⁴I_9/2 transition of Nd³⁺. The performance of YF₃:Nd³⁺ as an optical temperature sensor was evaluated using the full width at half maximum (FWHM), band broadening at 30% of maximum intensity (Δλ_30%), and valley-to-peak intensity ratio (VPR) techniques. All techniques demonstrated good repeatability and reproducibility. The best results were obtained using the VPR (V1/P1) method, which exhibited the highest relative sensitivity and the lowest temperature uncertainty, with values of 0.69 ± 0.02% K⁻¹ and 0.46 ± 0.09 K at 303 K, respectively. YF₃:Nd³⁺ shows promise as an optical temperature sensor operating entirely within the first biological window. Full article

Visual place recognition (VPR) is essential for robots and autonomous vehicles to understand their environment and navigate effectively. Inspired by face recognition, a recent trend for training a VPR model is to leverage classification objective, where the embeddings of images are trained to be similar to corresponding class centers. Ideally, the predicted similarities should be negative correlated to the geographic distances. However, previous studies typically used loss functions from face recognition due to the similarity between the two tasks, which cannot guarantee the rank consistency above as face recognition is unrelated to geographic distance. Current methods for distance-similarity or ordinal constraint are either for sample-to-sample training, only partially meet the constraint, or are incapable for the VPR task. To this end, we provide a mathematical definition geographic distance consistent defining the above consistency that the loss function for VPR should adhere to. Based on it, we derive the upper bound of cross-entropy softmax loss under the desired constraint to minimize, and propose a novel loss function for VPR that is geographic distance consistent, called GDCPlace. To the best of our knowledge, GDCPlace is the first classification loss function designed for VPR. To evaluate our loss, we collected 11 benchmarks that have high domain variability to test on. As our contribution is on the loss function and previous classification-based VPR methods mostly adopt face recognition loss function, we collect several additional loss functions to compare, e.g., loss for face recognition, image retrieval, ordinal classification, and general purpose. The results show that GDCPlace performs the best among different losses and former state-of-the-art (SOTA) for VPR. It is also evaluated for ordinal classification tasks to show the generalizability of GDCPlace. Full article

The task of visual geo-localization based on street-view images estimates the geographical location of a query image by recognizing the nearest reference image in a geo-tagged database. This task holds considerable practical significance in domains such as autonomous driving and outdoor navigation. Current approaches typically use perspective street-view images as reference images. However, the lack of scene content resulting from the restricted field of view (FOV) in such images is the main cause of inaccuracies in matching and localizing the query and reference images with the same global positioning system (GPS) labels. To address this issue, we propose a perspective-to-panoramic image visual geo-localization framework. This framework employs 360° panoramic images as references, thereby eliminating the issue of scene content mismatch due to the restricted FOV. Moreover, we propose the structural feature enhancement (SFE) module and integrate it into LskNet to enhance the ability of the feature extraction network to capture and extract long-term stable structural features. Furthermore, we propose the adaptive scene alignment (ASA) strategy to address the issue of data capacity and information content asymmetry between perspective and panoramic images, thereby facilitating initial scene alignment. In addition, a lightweight feature aggregation module, MixVPR, which considers spatial structure relationships, is introduced to aggregate the scene-aligned region features into robust global feature descriptors for matching and localization. Experimental results demonstrate that the proposed model outperforms current state-of-the-art methods and achieves R@1 scores of 72.5% on the Pitts250k-P2E dataset and 58.4% on the YQ360 dataset, indicating the efficacy of this approach in practical visual geo-localization applications. Full article

Melanoma cells remain resistant to chemotherapy with cisplatin (CisPt) and doxorubicin (DOX). The abnormal expression of Receptor-Interacting Protein Kinase 4 (RIPK4) in certain melanomas contributes to tumour growth through the NFκB and Wnt/β-catenin signalling pathways, which are known to regulate chemoresistance and recurrence. Despite this, the role of RIPK4 in response to chemotherapeutics in melanoma has not been reported. In this study, we examined how the downregulation and overexpression of RIPK4 affect the sensitivity of BRAF-mutated melanoma cells (A375 and WM266.4) to CisPt and DOX along with determining the underlying mechanism. Using two RIPK4 silencing methods (siRNA and CRISPR/Cas9) and overexpression (dCas9-VPR), we assessed CisPt and DOX-induced apoptosis using caspase 3/7 activity, annexin V/7AAD staining, and FASC analysis. In addition, qRT-PCR and Western blotting were used to detect apoptosis-related genes and proteins such as cleaved PARP, p53, and cyclin D1. We demonstrated that the overexpression of RIPK4 inhibits, while its downregulation enhances, CisPt- or DOX-induced apoptosis in melanoma cells. The effects of downregulation are similar to those observed with pre-incubation with cyclosporin A, an ABCG2 inhibitor. Additionally, our findings provide preliminary evidence of crosstalk between RIPK4, BIRC3, and ABCG2. The results of these studies suggest the involvement of RIPK4 in the observed resistance to CisPt or DOX. Full article