Virus Infection Research Articles

PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras.

In the realm of oncology, the transformative impact of PROTAC (PROteolysis TAgeting Chimeras) technology has been particularly pronounced since its introduction in the 21st century. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest in addressing a diverse array of medical conditions. This expanded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders. This comprehensive review explores the broadening landscape of PROTAC application, highlighting ongoing developments and innovations aimed at deploying these molecules across a spectrum of diseases. Careful consideration of the design challenges associated with PROTACs reveals that, when appropriately addressed, these compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives. To evaluate the efficacy of PROTAC molecules, a diverse array of assays is employed, ranging from High-Throughput Imaging (HTI) assays to Cell Painting assays, CRBN engagement assays, Fluorescence Polarization assays, amplified luminescent proximity homogeneous assays, Timeresolved fluorescence energy transfer assays, and Isothermal Titration Calorimetry assays. These assessments collectively contribute to a nuanced understanding of PROTAC performance. Looking ahead, the trajectory of PROTAC technology suggests its potential recognition as a versatile therapeutic strategy for an expansive range of medical conditions. Ongoing progress in this field sets the stage for PROTACs to emerge as valuable tools in the multifaceted landscape of medical treatments.

Advancing respiratory virus diagnostics: integrating the nasal IFN-I score for improved viral detection

BackgroundThis study aimed to demonstrate the utility of the nasal Type I interferon (IFN-I) response as a marker for respiratory viral infections (RVIs) and its potential to enhance diagnosis when combined with first-line PCR tests for Influenza A/B, RSV, and SARS-CoV-2. MethodsNasopharyngeal swabs (NPS) from patients at Hospices Civils de Lyon (November 2022 - April 2024) suspected of viral infections (n=788) and from healthy controls (n=53) were analysed. The IFN-I score was measured using the FILMARRAY® IFN-I pouch prototype, which detects four interferon-stimulated genes. The study evaluated the performance of the IFN-I score in detecting samples positive for viruses by first-line PCR and assessed its benefit in diagnosing RVIs in samples initially classified as negative by PCR. FindingsOut of 788 NPS included, 504 (64%) were positive with the first-line PCR tests, and IFN-I score was significantly higher in those samples (median [IQR]: 13·00 [2·76-45·40]) compared to ones collected from healthy controls (1·09 [0·67-1·30]; p<0.0001), with an area under the curve (AUC; 95%CI) of 0·92 (0·90-0·92). Moreover, out of the 284 NPS negative with first-line PCR tests, suspicion of viral infection according to IFN-I score was found in 63% of cases (178/284). Second-line test (BioFire® Respiratory Panel 2·1 plus) and viral metagenomic confirmed the presence of viruses 94% of cases. InterpretationThe study highlights the potential of integrating nasal IFN-I score into clinical workflows to improve RVI diagnosis and enhance preparedness for emerging viruses. FundingPublic grant overseen by the French National Research Agency (ANR21-RHUS-08/ANR-23-CHIN-0001).

Autopsy findings in cancer patients infected with SARS-CoV-2 show a milder presentation of COVID-19 compared to non-cancer patients.

COVID-19, caused by SARS-CoV-2, manifests with differing severity across distinct patient subgroups, with outcomes influenced by underlying comorbidities such as cancer, which may cause functional and compositional alterations of the immune system during tumor progression. We aimed to investigate the association of SARS-CoV-2 infection and its complications with cancer in a large autopsy series and the role of COVID-19 in the fatal sequence leading to death. A total of 2641 adult autopsies were investigated, 539 of these were positive for SARS-CoV-2. Among the total number of patients analyzed, 829 had active cancer. Overall, the cohort included 100 patients who simultaneously had cancer and SARS-CoV-2 infection. The course of COVID-19 was less severe in cancer patients, including a significantly lower incidence of viral and bacterial pneumonia, occurring more frequently as a contributory disease or coexisting morbidity, or as SARS-CoV-2 positivity without viral disease. SARS-CoV-2 positivity was more frequent among non-metastatic than metastatic cancer cases, and in specific tumor types including hematologic malignancies. COVID-19 was more frequently found to be directly involved in the fatal sequence in patients undergoing active anticancer therapy, but less frequently in perioperative status, suggesting that the underlying malignancy and consequent surgery are more important factors leading to death perioperatively than viral disease. The course of COVID-19 in cancer patients was milder and balanced during the pandemic. This may be due to relative immunosuppressed status, and the fact that even early/mild viral infections can easily upset their condition, leading to death from their underlying cancer or its complications.

Anti-viral Application of Ganoderma lucidum in COVID-19

Abstract: Ganoderma lucidum (Lingzhi), a common medicinal fungus, has been utilized in China since ancient times for health promotion and longevity. It has anti-inflammatory, antiviral, antitumor, antioxidant, and antiallergic activities. The antioxidant and immunomodulatory effects of this mushroom have shown promising impacts in the treatment of some viral diseases. COVID-19 is a life-threatening disease caused by SARS-CoV-2 that has recently been pandemic. Modern medicines have not been very efficient in the direct treatment of these viral infections, and although vaccination is effective in preventing viral infections, the incidence of acute respiratory infection can be reduced only slightly. Thus, alternative therapies are required, and in this regard, stimulating the immune system can be an effective way to prevent these infections. This study reports the potential of natural fungus-derived compounds that can possibly be used to fight SARS-CoV-2 infections.

Dominance of dengue virus serotype-2 in Pakistan (2023-2024): Molecular characterization of the envelope gene and exploration of antiviral targets.

Dengue virus infection, caused by a single positive-stranded RNA virus from the Flaviviridae family, represents a significant public health challenge in tropical and subtropical regions. This virus has four serotypes (DENV-1, 2, 3, and 4), primarily transmitted by Aedes mosquitoes. Despite extensive research, effective antiviral treatments and vaccines remain elusive due to the viral diversity and the complex mechanisms such as antibody-dependent enhancement (ADE). In the current study, NS1-positive serum samples from dengue cases in Pakistan (2023-2024), were analyzed to determine the predominant serotype and characterize the envelope (E) gene for further exploration of antiviral targets. Out of 100 samples, 63 (63%) tested positive for DENV-2, indicating its predominance during this period, while two samples showed mixed infections with DENV-2 and DENV-3. The envelope gene was successfully amplified using nested PCR, validated through gel electrophoresis and sanger sequencing. Phylogenetic analysis revealed high similarity of the DENV-2 isolates to strains from China and India. Computational modeling of the envelope protein structure identified potential antiviral binding sites and further molecular docking studies suggested that specific antiviral compounds like Arbidol and Quercetin can inhibit early steps in viral infection. Additionally, BepiPred-3.0 predicted several B-cell epitopes, which could be useful for vaccine development. These findings enhance our understanding of dengue epidemiology in Pakistan and contribute to the development of targeted antiviral therapies, potentially informing future vaccination strategies and outbreak management.

Deciphering the Underlying Mechanisms of Sanleng-Ezhu for the Treatment of Idiopathic Pulmonary Fibrosis Based on Network Pharmacology and Single-cell RNA Sequencing Data.

To decipher the underlying mechanisms of Sanleng-Ezhu for the treatment of idiopathic pulmonary fibrosis based on network pharmacology and single-cell RNA sequencing data. Idiopathic Pulmonary Fibrosis (IPF) is the most common type of interstitial lung disease. Although the combination of herbs Sanleng (SL) and Ezhu (EZ) has shown reliable efficacy in the management of IPF, its underlying mechanisms remain unknown. Based on LC-MS/MS analysis and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, we identified the bioactive components of SL-EZ. After obtaining the IPF-related dataset GSE53845 from the Gene Expression Omnibus (GEO) database, we performed the differential expression analysis and the weighted gene co-expression network analysis (WGCNA), respectively. We obtained lowly and highly expressed IPF subtype gene sets by comparing Differentially Expressed Genes (DEGs) with the most significantly negatively and positively related IPF modules in WGCNA. Subsequently, we performed Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on IPF subtype gene sets. The low- and highexpression MCODE subgroup feature genes were identified by the MCODE plug-in and were adopted for Disease Ontology (DO), GO, and KEGG enrichment analyses. Next, we performed the immune cell infiltration analysis of the MCODE subgroup feature genes. Single-cell RNA sequencing analysis demonstrated the cell types which expressed different MCODE subgroup feature genes. Molecular docking and animal experiments validated the effectiveness of SL-EZ in delaying the progression of pulmonary fibrosis. We obtained 5 bioactive components of SL-EZ as well as their corresponding 66 candidate targets. After normalizing the samples of the GSE53845 dataset from the GEO database source, we obtained 1907 DEGs of IPF. Next, we performed a WGCNA analysis on the dataset and got 11 modules. Notably, we obtained 2 IPF subgroups by contrasting the most significantly up- and down-regulated modular genes in IPF with DEGs, respectively. The different IPF subgroups were compared with drugcandidate targets to obtain direct targets of action. After constructing the protein interaction networks between IPF subgroup genes and drug candidate targets, we applied the MCODE plug-in to filter the highest-scoring MCODE components. DO, GO, and KEGG enrichment analyses were applied to drug targets, IPF subgroup genes, and MCODE component signature genes. In addition, we downloaded the single-cell dataset GSE157376 from the GEO database. By performing quality control and dimensionality reduction, we clustered the scattered primary sample cells into 11 clusters and annotated them into 2 cell subtypes. Drug sensitivity analysis suggested that SL-EZ acts on different cell subtypes in IPF subgroups. Molecular docking revealed the mode of interaction between targets and their corresponding components. Animal experiments confirmed the efficacy of SL-EZ. We found SL-EZ acted on epithelial cells mainly through the calcium signaling pathway in the lowly-expressed IPF subtype, while in the highly-expressed IPF subtype, SL-EZ acted on smooth muscle cells mainly through the viral infection, apoptosis, and p53 signaling pathway.

Darya's disease: rare dermatosis with complicated manifestations

The pathogenesis of the disease is associated with mutations in the ATP2A2 gene of chromosome 12q23-24, which disrupt intracellular calcium metabolism. COVID-19 infection is known to cause a cytokine storm characterized by increased levels of tumor necrosis factor (TNF), interleukin (IL) 6 and 1β. TNF and IL-6 additionally reduce the activity of type 2 calcium ATPase in patients with Darye's disease. The typical clinical picture of rare hereditary dermatosis is characterized by hyperkeratotic papules located in seborrheic zones. Papules tend to fuse to form plaques. The surfaces of the palms and soles are also a frequent localization of the pathological process. Papules may grow into hypertrophic vegetations, damage to nails and oral mucosa, and the addition of secondary bacterial and viral infections. The typical course is of a continuous progressive nature with periods of exacerbation and incomplete remission. Systemic retinoids are the basis of therapy for Darye's disease. In addition, glucocorticosteroids and cyclosporine are systematically used. Local therapy includes keratolytic and antiseptic drugs, emollients. A case of clinical observation of a 39-year-old patient with Darye's disease is presented. The diagnosis was made based on the analysis of complaints, anamnesis, objective and local status, dermatoscopic picture, laboratory and histological examination. Against the background of ongoing therapy, the patient was discharged with clinical improvement and continues treatment on an outpatient basis. The clinical observation of this case is of interest to practicing dermatovenerologists.

The Relationship Between Prenatal, Perinatal, and Postnatal Factors and ADHD: The Role of Nutrition, Diet, and Stress.

Attention-Deficit Hyperactive Disorder (ADHD) is a neurobehavioral syndrome affecting children aged 6-17 with symptoms manifesting before age 12. ADHD presents heterogeneously and is associated with various psychiatric disorders. The cause remains elusive, but genetic and environmental factors, brain region maturation delays, and neurotransmitter dysregulation are implicated. Effective treatment requires a multi-disciplinary approach, primarily involving pharmacological and behavioral intervention. Stimulants like methylphenidate and amphetamines are first-line medications, but non-stimulants may be considered for some patients. However, stimulants face challenges related to misuse, dependence, and long-term tolerability issues. The etiology of ADHD involved genetic predisposition, environmental influences, and prenatal, perinatal, and postnatal factors. Prenatal causes encompass maternal diet, alcohol consumption, viral infections, and stress. Postnatal factors include head trauma, meningitis, toxin, nutritional deficiencies, as well as iodine deficiency and hypothyroidism. The gut microbiome's role in ADHD is emerging, influencing neurodevelopment through microbiota-gut-brain axis. Understanding these diverse etiological factors is essential for comprehensive ADHD management.

Potential role of bacterial extracellular vesicles in the pathophysiology of systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a rare autoimmune disorder influenced by various factors, including infections. Following bacterial or viral infections, there is an increase in IFN-I production, primarily by plasmacytoid dendritic cells (pDCs). Overproduction of IFN-I has been shown to drive the progression of SLE. Recent findings indicate that the gene expression signature of IFN-I in lupus nephritis patients does not co-occur with pDCs as expected; instead, it is localized in glomerular regions with anastomosing capillaries, suggesting a potential source from the blood. T cells, natural killer cells, and myeloid lineage cells may also secrete IFN in the bloodstream. Bacterial presence in the bloodstream challenges the concept of blood sterility, raising the possibility that cell-free microbial components, such as bacterial extracellular vesicles (BEVs), could trigger excessive IFN production through systemic circulation. While existing studies suggest a role for BEVs in human SLE, experimental evidence has yet to establish a direct association between the entire BEV nanoparticle and the disease. Research has primarily focused on (1) mammalian EVs and (2) purified eDNA and other specific cargoes as contributors to SLE progression. It remains unproven whether these bacterial molecules exert their effects while associated with vesicular membranes, i.e., BEVs. We hypothesize that BEVs, which carry diverse cargoes including nucleic acids, may enter systemic circulation, induce cellular responses leading to IFN overproduction, and exacerbate SLE severity. Clinical studies could investigate the association of BEVs with SLE progression by monitoring their presence and quantity in blood samples and correlating these factors with disease outcomes. Furthermore, understanding the involvement of BEVs may aid in identifying SLE biomarkers, inform infection prevention strategies, and inspire the development of BEV-neutralizing agents.

Heartland Virus Infection in Elderly Patient Initially Suspected of Having Ehrlichiosis, North Carolina, USA.

We report a patient in North Carolina, USA, with Heartland virus infection whose diagnosis was complicated by previous Ehrlichia chaffeensis infection. We identified E. ewingii-infected and Bourbon virus-infected tick pools at the patient's residence. Healthcare providers should consider testing for tickborne viruses if ehrlichiosis is suspected.

1α,25-hydroxyvitamin D3 alleviated rotavirus infection induced ferroptosis in IPEC-J2 cells by regulating the ATF3-SLC7A11-GPX4 axis

Rotavirus (RV) mainly infects mature intestinal epithelial cells and impairs intestinal absorption function, which leads to the death of infected cells and eventually fatal diarrhea. Ferroptosis is a novel regulatory cell death pattern, which can be caused by virus infection. 1α,25-hydroxyvitamin D3 (1,25D3) has an anti-RV infection effect and can regulate ferroptosis. However, whether RV infection can induce ferroptosis, and whether 1,25D3 can inhibit RV infection by regulating ferroptosis has not yet been studied. Present study shows that RV infection or erastin treatment induces IPEC-J2 cell death, which results in mitochondrial shrinkage, decreased mitochondrial membrane potential (MMP) and glutathione (GSH) content, increased MMP, intracellular Fe2+, reactive oxygen species (ROS), and malondialdehyde (MDA) contents. Meanwhile, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), and deferoxamine (DFO) treatment can effectively reverse the increase of intracellular Fe2+, ROS and MDA levels induced by RV infection. Moreover, RV infection increases activating transcription factor 3 (ATF3) mRNA and protein expressions, and inhibited SLC7A11 and glutathione peroxidase 4 (GPX4) expressions, which was partially alleviated by siATF3. 1,25D3 treatment significantly eliminates RV induced ferroptosis via ATF3-SLC7A11-GPX4 axis. Therefore, our results reveals that RV infection induces ferroptosis in IPEC-J2 cell and 1,25D3 alleviates RV induced ferroptosis by regulating the ATF3-SLC7A11-GPX4 axis.

Study on the Clinical Characteristics, Persistent Infection Ability and Viral Load of Human Papillomavirus Type 73 Single Infection.

Human papillomavirus (HPV) infection is a main cause of cervical cancer. Different HPV types exhibit significant differences in pathogenicity. Clinical data on HPV73 single infection is limited, this study aimed to analyze the clinical characteristics of HPV73 single infections. We collected cervical exfoliated cells to examine the infection rate and the clinical characteristics of patients with single HPV73 infection, and to investigate the association of viral load, persistent infection, and pathogenicity. The positive rate of HPV73 among women tested was approximately 0.14% (609/435 072). Among 214 HPV73 single infection cases, the number of patients with normal cytology, cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and cervical cancer were 182, 24, 5, 1, and 1, respectively. Follow-up data showed that 14.29% (3/21) of CIN1 patients developed to higher-grade lesions, with 3.73% (5/134) of normal patients progressed to CIN. The viral load in the CIN group was significantly higher than that in the normal group (p = 0.001), and the viral load in the persistent infection group was significantly higher than that of the viral-clearance group (p < 0.001). HPV73 single infection can lead to cervical cancer, with relatively low pathogenicity. And high viral load is a crucial factor in its persistent infection and pathogenicity.

Opportunities and Regulatory Challenges of Functional Foods and Nutraceuticals During COVID-19 Pandemic

: The novel Coronavirus has brought global mortality, disruption, and a significant loss of life. A compromised immune system is a known risk factor for all viral influenza infections. Due to the perceived “immune-boosting” properties of nutraceutical products, sales of dietary supplements have grown globally. In recent years, consumers have increasingly demanded nutraceutical products rather than curative synthetic medicines for preventive therapies for the coronavirus disease outbreak of 2019 (COVID-19). Healthy foods and nutraceuticals have become daily diet plans for consumers. Although there has been an increase in demand, there is no such regulation and harmonized process, which stands as a barrier to the approval of these products. Therefore, many misbranded and spurious products are entering the market, which may harm consumers. This article focuses on the role of functional foods and nutraceutical in the management of COVID-19 also focuses on the different nutraceutical regulations in each country and compare the similarities and differences of the following countries: India, the USA (United States of America), the EU (European Union), and China. The comparative study of nutraceutical regulations in India, the USA, Europe, and China shows that there is a difference regarding the nutraceutical regulations; however, despite the differences, it is observed that it has the same underlying objective, i.e., ensuring the safety of the consumers by maintaining the product quality.

In-depth Chemistry and Pharmacological Potential of Propolis: A Critical Review of Recent Developments

Background: One of the most popular beekeeping products is propolis. The word "propolis," which alludes to a beehive, has Greek sources and implies "defense for the community." Propolis is a resinous material that honey worker bees (Apis mellifera L.) and other bee species make for a variety of uses. Since 300 BC, propolis has been used as a traditional remedy. Various pharmacological effects of distinct propolis extracts as well as those of its ingredients, including antioxidant, antiulcer, anticancer, antiviral, anti-microbial, anti-inflammatory, and antifungal characteristics, have recently been identified. Objective: In this review article, we focus on the origin, recent advances in the chemical constituents, and new therapeutic potential of propolis. Material and Methods: An exhaustive analysis of the literature search was conducted. The standard keywords "propolis," "origin," "chemical constituents," "pharmacological activity," "recent advances," and "traditional uses" have been used to search a variety of the standard databases, such as Scopus and Elsevier, PubMed, ScienceDirect, and Science Web, for research and review articles published between 1998 and 2023. Results: This review article included over 150 articles (research and reviews) that were appraised and researched. Conclusion: Since 2012, more than 300 substances have been shown to have pharmacological action against a variety of illnesses, including cancer, inflammation, ulcers, wound healing, diabetes, bacterial, viral, and fungal infections, hepatic disorders, dental problems, brain diseases, etc. Overall, propolis may be considered a source of bioactive compounds for pharmaceutical development. Future studies should consider plant types, regional conditions, bee subspecies, and variations.

Clinical outcomes of untreated adults living with chronic hepatitis B in The Gambia: an analysis of data from the prospective PROLIFICA cohort study

Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis. Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011-14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma. 943 HBsAg-positive people with chronic hepatitis B were recruited to the PROLIFICA study. Of these 943, 58 (6%) fulfilled 2012 EASL treatment eligibility criteria at baseline, 35 (4%) were ineligible for treatment but received antiviral therapy, and 44 (5%) were immediately lost to follow-up. Thus, 806 (85%) participants were analysed for the primary outcome (486 [60%] were male and 320 [40%] were female). After a median follow-up of 6·11 years (IQR 5·34-6·80), 708 (88%) participants were confirmed to be alive at last surveillance, 71 (9%) were lost to follow-up and were censored, and 27 (3%) died, giving an all-cause mortality rate of 582 per 100 000 person-years (95% CI 399-849). Of the 27 people who died, five (19%) had liver-related deaths. Of 708 participants confirmed to be alive, 544 (77%) attended follow-up and were assessed for the secondary outcome. Disease progression occurred in 36 (7%) participants: five (1%) became newly eligible for antiviral therapy per EASL 2017 criteria without liver fibrosis progression; 18 (3%) had liver fibrosis progression alone; 13 (2%) had liver fibrosis progression and newly fulfilled the treatment criteria; and none had hepatic decompensation or developed hepatocellular carcinoma. In multivariable analysis adjusted for sex and age, only a baseline HBV DNA of 20 000 IU/mL or more, compared with the baseline HBV DNA of 2000 IU/mL or lower as the reference, was significantly associated with liver disease progression (odds ratio 5·39, 95% CI 1·37-21·23). Among people with chronic hepatitis B who were ineligible for antiviral therapy in The Gambia, all-cause mortality and liver disease progression were low. The clinical benefit of expanding antiviral therapy in this subgroup of patients remains uncertain. European Commission, Medical Research Council UK Research and Innovation, and Gilead Sciences.

Predicting hepatitis C infection with machine learning algorithms: a prospective study

&lt;p&gt;Globally, chronic hepatitis C virus (HCV) infection affects millions of people and leads to a high number of deaths annually. In 2019, the World Health Organization (WHO) recorded around 290,000 deaths related to HCV, a virus transmitted mainly through blood that causes liver damage. The virus has infected more than 169 million people worldwide. This study aims to compare the performance of machine learning (ML) models for HCV detection. ML models such as logistic regression (LR), random forest (RF), decision tree (DT), and catBoost classifier (CATBC) were used. To carry out this task, a dataset of 615 patient records, and 14 variables were used. This research process was carried out in multiple phases, encompassing model understanding, data analysis and cleaning, ML model training, and subsequent model evaluation. The results revealed that the gradient boosting (GB) model stood out by achieving the best performance and highest accuracy, achieving a rate of 94% in HCV detection, this demonstrates outstanding performance compared to the other models such as LR, RF, k-nearest neighbor (KNN), DT, and CATBC, which obtained accuracy rates of 89%, 93%, 85%, 93%, 93%, and 92%, respectively. It can be concluded that the GB model stands out as the best algorithm for this task.&lt;/p&gt;

Purification and Characterization of Kyasanur Forest Disease Virus EDIII domain of major Envelope Glycoprotein

Current research efforts are underway to create novel approaches for the efficient diagnosis, monitoring, and mitigation of Kyasanur Forest Disease Virus (KFDV) infections. Flavivirus subunit-based vaccines based on envelope glycoprotein EDIII are now in preclinical and clinical research stages. Efficient purification and isolation methods for surface immunogenic viral antigens, including the recombinant envelope immunoglobulin-like domain III (rEDIII) protein, are crucial for the production and manufacturing of promising vaccine candidates that have been extensively assessed in previous literature. Here, we describe a method for high-yield expression, purification, and refolding of a KFDV rEDIII protein from a bacterial expression system. The KFDV rEDIII protein is extracted from the inclusion bodies in urea denaturing buffer followed by nickel-nitrilotriacetic acid (Ni-NTA) affinity chromatography. The purified, denatured KFDV rEDIII protein was subsequently refolded using a step-wise gradient urea dilution via the dialysis method. The circular dichroism and Fourier transform infrared spectroscopy analysis confirms that the refolded KFDV rEDIII maintains the native secondary conformation majorly containing β-strands. Our study provides valuable insights into the design and expression strategies of rEDIII as a novel subunit vaccine candidate against KFDV.

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Globally, nearly half of all pregnancies are unintended, ∼1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy and two highly prevalent sexually transmitted infections (STIs).

A multidomain PARP14 construct suitable for bacterial expression.

Poly-ADP-ribose polymerase-14 (PARP14) can modify proteins and nucleic acids by the reversible addition of a single ADP-ribose molecule. Aberrant PARP14 functions have been related to cancer and inflammation, and its domains are involved in processes related to viral infection. Previous research indicates that PARP14 functions might be mediated via a multitude of target proteins. In vitro studies of this large multidomain enzyme have been complicated by difficulties to obtain biochemical quantities of pure protein. Here we present a strategy that allows bacterial expression and purification of a functional multidomain construct of PARP14. We substituted an internal KH domain and its neighboring unstructured region with a SUMO domain to obtain a protein construct that encompasses three macrodomains, a WWE domain, and a PARP catalytic domain. We show that the resulting construct retains both ADP-ribosyltransferase and de-MARylase activities. This construct will be useful in structural and functional studies of PARP14.

Deciphering the Molecular Landscape of Dengue Infection: Insights from gene expression profiling and Protein Interactions

Dengue fever (DF) is a viral infection recognized as one of the most rapidly spreading vector-borne diseases among humans. However, the molecular mechanisms underlying disease aetiology and potential therapeutic targets remain unclear. This study presents a thorough examination of differentially expressed genes (DEGs) throughout the spectrum of Dengue infection stages, offering insights into disease mechanisms and therapeutic targets. Through meticulous analysis of DEGs within each infection stage, key genes pertinent to disease progression are identified, highlighting their roles in host-virus interactions. Noteworthy discoveries include the upregulation of IFI27 and USP18 in mild infection, suggesting involvement in viral replication inhibition and host defence, alongside the downregulation of CMTM2, indicating alterations in immune-related functions. Similarly, in severe infection, upregulated genes like IGHV1-69 are linked to illness severity, while downregulated IL-13RA1 signifies disruptions in cytokine signaling. Overlapping DEGs between infection groups unveil shared biological processes, further elucidated through functional enrichment analysis, showcasing coordinated regulation of cellular processes and pathways. Integration of Dengue virus and human interaction network analysis reveals crucial insights into the mechanisms by which the virus mediates the disease progression and offers potential therapeutic opportunities for disease management.