Inhibition of B cell receptor signaling induced by the human adenovirus species D E3/49K protein.

Introduction: The early transcription unit 3 (E3) of human adenoviruses (HAdVs) encodes several immunoevasins, including the E3/49K protein, which is unique for species D of HAdVs. It is expressed as surface transmembrane protein and shed. E3/49K of HAdV-D64 binds to the protein tyrosine phosphatase surface receptor CD45, thereby modulating activation of T and NK cells. Methods: Considering that E3/49K represents the most polymorphic viral protein among species D HAdVs, we demonstrate here that all tested E3/49K orthologs bind to the immunologically important regulator CD45. Thus, this feature is conserved regardless of the pathological associations of the respective HAdV types. Results: It appeared that modulation of CD45 is a unique property restricted to HAdVs of species D. Moreover, E3/49K treatment inhibited B cell receptor (BCR) signaling and impaired BCR signal phenotypes. The latter were highly comparable to B cells having defects in the expression of CD45, suggesting E3/49K as a potential tool to investigate CD45 specific functions. Conclusion: We identified B cells as new direct target of E3/49K-mediated immune modulation, representing a novel viral immunosubversive mechanism.

The study of new fixed-point iteration schemes for solving absolute value equations.

Absolute value equations (AVEs) play a crucial role in solving various complexities across scientific computing, engineering, management science, and operations research. This article presents two fixed-point iteration schemes designed for such AVEs. Furthermore, we show some convergence conditions under specific circumstances. Lastly, the theoretical findings are validated using numerical examples, which emphasize the distinct advantages offered by the newly developed schemes. These results are highly promising and may stimulate future research in this domain.

Optimal control of combination immunotherapy for a virtual murine cohort in a glioblastoma-immune dynamics model.

The immune checkpoint inhibitor anti-PD-1, commonly used in cancer immunotherapy, has not been successful as a monotherapy for the highly aggressive brain cancer glioblastoma. However, when used in conjunction with a CC-chemokine receptor-2 (CCR2) antagonist, anti-PD-1 has shown efficacy in preclinical studies. In this paper, we aim to optimize treatment regimens for this combination immunotherapy using optimal control theory. We extend a treatment-free glioblastoma-immune dynamics ODE model to include interventions with anti-PD-1 and the CCR2 antagonist. An optimized regimen increases the survival of an average mouse from 32 days post-tumor implantation without treatment to 111 days with treatment. We scale this approach to a virtual murine cohort to evaluate mortality and quality of life concerns during treatment, and predict survival, tumor recurrence, or death after treatment. A parameter identifiability analysis identifies five parameters suitable for personalizing treatment within the virtual cohort. Sampling from these five practically identifiable parameters for the virtual murine cohort reveals that personalized, optimized regimens enhance survival: 84% of the virtual mice survive to day 100, compared to 60% survival in a previously studied experimental regimen. Subjects with high tumor growth rates and low T cell kill rates are identified as more likely to die during and after treatment due to their compromised immune systems and more aggressive tumors. Notably, the MDSC death rate emerges as a long-term predictor of either disease-free survival or death.

Tissue, cellular, and molecular level determinants for eye lens stiffness and elasticity.

The eye lens is a transparent, ellipsoid tissue in the anterior chamber that is required for the fine focusing of light onto the retina to transmit a clear image. The focusing function of the lens is tied to tissue transparency, refractive index, and biomechanical properties. The stiffness and elasticity or resilience of the human lens allows for shape changes during accommodation to focus light from objects near and far. It has long been hypothesized that changes in lens biomechanical properties with age lead to the loss of accommodative ability and the need for reading glasses with age. However, the cellular and molecular mechanisms that influence lens biomechanical properties and/or change with age remain unclear. Studies of lens stiffness and resilience in mouse models with genetic defects or at advanced age inform us of the cytoskeletal, structural, and morphometric parameters that are important for biomechanical stability. In this review, we will explore whether: 1) tissue level changes, including the capsule, lens volume, and nucleus volume, 2) cellular level alterations, including cell packing, suture organization, and complex membrane interdigitations, and 3) molecular scale modifications, including the F-actin and intermediate filament networks, protein modifications, lipids in the cell membrane, and hydrostatic pressure, influence overall lens biomechanical properties.

SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development.

SLC30A9 (ZnT9) is a mitochondria-resident zinc transporter. Mutations in SLC30A9 have been reported in human patients with a novel cerebro-renal syndrome. Here, we show that ZnT9 is an evolutionarily highly conserved protein, with many regions extremely preserved among evolutionarily distant organisms. In Drosophila melanogaster (the fly), ZnT9 (ZnT49B) knockdown results in acutely impaired movement and drastic mitochondrial deformation. Severe Drosophila ZnT9 (dZnT9) reduction and ZnT9-null mutant flies are pupal lethal. The phenotype of dZnT9 knockdown can be partially rescued by mouse ZnT9 expression or zinc chelator TPEN, indicating the defect of dZnT9 loss is indeed a result of zinc dyshomeostasis. Interestingly, in the mouse, germline loss of Znt9 produces even more extreme phenotypes: the mutant embryos exhibit midgestational lethality with severe development abnormalities. Targeted mutagenesis of Znt9 in the mouse brain leads to serious dwarfism and physical incapacitation, followed by death shortly. Strikingly, the GH/IGF-1 signals are almost non-existent in these tissue-specific knockout mice, consistent with the medical finding in some human patients with severe mitochondrial deficiecny. ZnT9 mutations cause mitochondrial zinc dyshomeostasis, and we demonstrate mechanistically that mitochondrial zinc elevation quickly and potently inhibits the activities of respiration complexes. These results reveal the critical role of ZnT9 and mitochondrial zinc homeostasis in mammalian development. Based on our functional analyses, we finally discussed the possible nature of the so far identified human SLC30A9 mutations.

Fam49b dampens TCR signal strength to regulate survival of positively selected thymocytes and peripheral T cells.

The fate of developing T cells is determined by the strength of T cell receptor (TCR) signal they receive in the thymus. This process is finely regulated through the tuning of positive and negative regulators in thymocytes. The Family with sequence similarity 49 member B (Fam49b) protein is a newly discovered negative regulator of TCR signaling that has been shown to suppress Rac-1 activity in vitro in cultured T cell lines. However, the contribution of Fam49b to the thymic development of T cells is unknown. To investigate this important issue, we generated a novel mouse line deficient in Fam49b (Fam49b-KO). We observed that Fam49b-KO double positive (DP) thymocytes underwent excessive negative selection, whereas the positive selection stage was unaffected. Fam49b deficiency impaired the survival of single positive thymocytes and peripheral T cells. This altered development process resulted in significant reductions in CD4 and CD8 single-positive thymocytes as well as peripheral T cells. Interestingly, a large proportion of the TCRγδ+ and CD8αα+TCRαß+ gut intraepithelial T lymphocytes were absent in Fam49b-KO mice. Our results demonstrate that Fam49b dampens thymocytes TCR signaling in order to escape negative selection during development, uncovering the function of Fam49b as a critical regulator of the selection process to ensure normal thymocyte development and peripheral T cells survival.

In vitro characterization of probiotic potential of Lactobacillus plantarum CM49 against selected cattle mastitogens.

BACKGROUND: Bovine mastitis results in significant economic losses for the dairy industry globally due to milk production losses and decreased herd efficiency. This research aimed to isolate, select, and characterize indigenous lactobacilli with probiotic properties. A total of 40 lactobacilli were isolated from healthy milk samples of cattle and identified at the species level through 16S rDNA sequencing. All isolates were initially screened for antimicrobial activity, and selected isolates underwent in vitro assessment of probiotic properties. RESULTS: Among the lactobacilli isolates, varying levels of activity (9 to 19 mm) against cattle mastitogens; Stapylococcus aureus (Staph. aureus), Escherichia coli (E. coli) and Streptococcus dysgalactiae (Strep. dysgalactiae) were observed in the well diffusion assay. These isolates demonstrated auto-aggregation (ranging from 14.29 ± 0.96% to 62.11 ± 1.09%) and co-aggregate (ranging from 9.21 ± 0.14% to 55.74 ± 0.74%) with mastitogens after 2 h. Lactobacillus (Lb.) plantarum CM49 showed sensitivity to most antibiotics tested and exhibited strong inhibitory effects, with mean log10 reductions of 3.46 for Staph. aureus, 2.82 for E. coli, and 1.45 for Strep. dysgalactiae in co-culture experiments. Furthermore, Lb. plantarum CM49 significantly decreased the adhesion rate of mastitogens on the bovine mammary cell line and mouse model, demonstrating its potential effectiveness in preventing mastitis. CONCLUSION: It is concluded that Lb. plantarum CM49 has remarkable probiotic potential with activity against cattle mastitogens in the laboratory and cell culture and competitively excludes mastitogens from bovine mammary cells and ameliorates Staph. aureus-induced mastitis in mice.

Description of three new HLA-B alleles: HLA-B*15:689, HLA-B*35:603 and HLA-B*49:01:25.

HLA-B*15:689, HLA-B*35:603 and HLA-B*49:01:25, three novel HLA class I alleles detected by next-generation sequencing.

Inhibitors and activators for myotoxic phospholipase A2-like toxins from snake venoms - A structural overview.

Snakebite envenomations result in acute and chronic physical and psychological health effects on their victims, leading to a substantial socio-economic burden in tropical and subtropical countries. Local necrosis is one of the serious effects caused by envenomation, primarily induced by snake venoms from the Viperidae family through the direct action of components collectively denominated as myotoxins, including the phopholipase A2-like (PLA2-like) toxins. Considering the limitations of antivenoms in preventing the rapid development of local tissue damage caused by envenomation, the use of small molecule therapeutics has been suggested as potential first-aid treatments or as adjuvants to antivenom therapy. In this review, we provide an overview of the structural interactions of molecules exhibiting inhibitory activity toward PLA2-like toxins. Additionally, we discuss the implications for the myotoxic mechanism of PLA2-like toxins and the molecules involved in their activation, highlighting key differences between activators and inhibitors. Finally, we integrate all these results to propose a classification of inhibitors into three different classes and five sub-classes. Taking into account the structural and affinity information, we compare the different inhibitors/ligands to gain a deeper understanding of the structural basis for the effective inhibition of PLA2-like toxins. By offering these insights, we aim to contribute to the search for new and efficient inhibitor molecules to complement and improve current therapy by conventional antivenoms.

Optimal vaccination strategies on networks and in metropolitan areas.

This study presents a mathematical model for optimal vaccination strategies in interconnected metropolitan areas, considering commuting patterns. It is a compartmental model with a vaccination rate for each city, acting as a control function. The commuting patterns are incorporated through a weighted adjacency matrix and a parameter that selects day and night periods. The optimal control problem is formulated to minimize a functional cost that balances the number of hospitalizations and vaccines, including restrictions of a weekly availability cap and an application capacity of vaccines per unit of time. The key findings of this work are bounds for the basic reproduction number, particularly in the case of a metropolitan area, and the study of the optimal control problem. Theoretical analysis and numerical simulations provide insights into disease dynamics and the effectiveness of control measures. The research highlights the importance of prioritizing vaccination in the capital to better control the disease spread, as we depicted in our numerical simulations. This model serves as a tool to improve resource allocation in epidemic control across metropolitan regions.

Could metformin modulate the outcome of chronic murine toxoplasmosis?

Toxoplasmosis is a pervasive parasitic infection possessing a chief impact on both public health and veterinary medicine. Unfortunately, the commercially-available anti-Toxoplasma agents have either serious side effects or diminished efficiency, specifically on the Toxoplasma tissue cysts. In the present study, metformin (The first-line treatment for type 2 diabetes mellitus) was investigated for the first time against chronic cerebral toxoplasmosis in mice model experimentally-infected with ME49 strain versus spiramycin. Two metformin regimens were applied; starting one week before the infection and four weeks PI. Parasitological, ultrastructural, histopathological, immunohistochemical, immunological, and biochemical assessments were performed. The anti-parasitic effect of metformin was granted by the statistically-significant reduction in tissue-cyst burden in both treatment regimens. This was accompanied by markedly-mutilated ultrastructure and profound amelioration of the cerebral histopathology with remarkable decline in the brain CD4+ and CD8+ T cell count. Besides, diminution of anti-Toxoplasma IgG and brain GSH levels was evident. Ultimately, the present findings highlighted the powerful promising therapeutic role of metformin in the management of chronic toxoplasmosis on a basis of anti-parasitic, anti-inflammatory, and anti-oxidant possessions.

First-in-human study to assess the safety, tolerability, and pharmacokinetics of intravenous SHPL-49 following single- and multiple-ascending-dose administration in healthy adults.

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300 mg) and multiple ascending doses (75-300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC0-t) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300 mg.

CCR5 Δ32 and CTLA-4 +49 A/G Gene Polymorphisms and Interferon-ß Treatment Response in Croatian and Slovenian Multiple Sclerosis Patients.

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-ß treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders (n = 173) and non-responders (n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence (p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-ß therapy in females (p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females (p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-ß treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients.

Characterisation of gradient flows for a given functional.

Let X be a vector field and Y be a co-vector field on a smooth manifold M. Does there exist a smooth Riemannian metric g α ß on M such that Y ß = g α ß X α ? The main result of this note gives necessary and sufficient conditions for this to be true. As an application of this result we provide a gradient-flow characterisation for dissipative quantum systems. Namely, we show that finite-dimensional ergodic Lindblad equations admit a gradient flow structure for the von Neumann relative entropy if and only if the condition of bkm-detailed balance holds.

Prevalence and factors associated with unskilled childbirth attendance in Guinea: Analysis of the 2018 Demographic and Health Survey.

This study aimed to analyze the prevalence and factors associated with the unassisted delivery by qualified health personnel in the Republic of Guinea, based on data from the 2018 demographic and health survey. Multivariate logistic regression was used to identify the associated factors. The prevalence of unassisted delivery was 40.8%; it was 38.4% in rural areas and 2.3% in urban areas. Factors associated with this type of delivery included the performance of no ANC (ORa = 6.19 IC95%: [4.86 - 7.87], p<0.001) and those who had performed one to three ANC (ORa =1.75 IC95%: [1.49 - 2.05], p<0.001) the perception of the distance to the health institution as a problem (ORa =1.28 IC95%: [1.10 - 1.48], p<0.001), belonging to the poor wealth index (ORa = 2.77 IC 95%: [2.19 - 3.50], p<0.001) and average (ORa = 2.01 IC95%: [1.57 - 2.57], p<0.001), the fact of residing in the region of Faranah (ORa = 2.24 IC95%: [1.37 - 3.65], p<0.001) and rural areas (ORa = 4.15 IC95%: [3.10 - 5.56], p<0.001). Strengthening community awareness, making functional ambulances available to rural health centers and making prenatal care inputs available in health institutions would help to reduce the scale of unassisted deliveries in the Republic of Guinea.

Cette étude visait à analyser la prévalence et les facteurs associés à l'accouchement non assisté par un personnel de santé qualifié en Guinée, partant des données de l'enquête démographique et de santé de 2018. La régression logistique multivariée a servi à identifier les facteurs associés. La fréquence de l'accouchement non assisté était de 40.8% ; elle était de 38.4% en milieu rural et 2.3% en milieu urbain. Les facteurs associés à ce type d'accouchement comprenaient la réalisation d'aucune CPN (ORa =6.19 IC95% : [4.86 - 7.87], p<0.001) et celles qui avaient réalisées une à trois CPN (ORa =1.75 IC95% : [1.49 - 2.05], p<0.001) la perception de la distance pour la structure de santé comme un problème (ORa =1.28 IC95% : [1.10 - 1.48], p<0.001), l'appartenance à l'indice de richesse pauvre (ORa =2.77 IC95% : [2.19 - 3.50], p<0.001) et moyenne (ORa =2.01 IC 95% : [1.57 - 2.57], p<0.001), le fait de résider dans la région de Faranah (ORa =2.24 IC95% : [1.37 - 3.65], p<0.001) et rurale (ORa =4,15 IC 95% : [3,10 - 5,56], p<0,001). Le renforcement de la sensibilisation communautaire, la mise d'ambulances fonctionnelles à la disposition des centres de santé ruraux et rendre disponible les intrants de soins prénatals dans les structures sanitaires contribueraient serte à réduire l'ampleur des accouchements non assistés en Guinée.

Optimal hybrid resonant current controller for microgrids connected to an unbalanced IEEE test distribution network.

Microgrids (MGs) based on renewable energies have emerged as a proficient strategy for tackling power quality issues in conventional distribution networks. Nonetheless, MG systems require a suitable control scheme to supply energy optimally towards the electrical grid. This paper presents an innovative framework for designing hybrid Proportional-Resonant (PR) controllers with Linear Quadratic Regulators (LQR), PR+LQR, which merge relevant properties of PR and LQR controllers. This method simultaneously determines the MG control parameters and the current unbalanced factor generated at the distribution network. We select the traditional IEEE 13-bus test feeder network and place two MGs at strategic locations to validate our approach. Moreover, we use the Grey Wolf Optimizer (GWO) to find control parameters through a reliable fitness function that leads to high-performance microgrids. Finally, we conceive several tests to assess the efficacy of GWO for tuning the hybrid controller and compare the resulting data across distinct realistic operation conditions representing power quality events. So, we choose four case studies considering different renewable energy penetration indexes and power factors and evaluate the effects of the MGs over the distribution grid. We also compare the proposed hybrid PR+LQR controller against closely-related alternatives from the literature and validate its robustness and stability through the disk margin approach and the Nyquist criterion. Our numerical simulations prove that hybrid controllers driven by GWO are highly reliable strategies, yielding an average unbalanced current reduction of 30.03%.

Advancing Pain Management Protocols for Intrauterine Device Insertion: Integrating Evidence-Based Strategies Into Clinical Practice.

The discomfort and anxiety associated with the intrauterine device (IUD) insertion process is a significant barrier to its adoption as a form of contraception despite its high efficacy. This study aimed to classify and identify methods for minimizing pain and anxiety in IUD implantation in women below the age of 49. A search of publications from online databases, PubMed and Google Scholar, revealed 14 articles that met the inclusion criteria. An analysis of the selected studies showed that several pharmacological and non-pharmacological measures effectively minimized patient discomfort associated with IUD insertion. Of the 14 studies, 12 evaluated pharmacological methods for pain management in IUD insertion, while two studies assessed non-pharmacological methods. The results showed that although the IUD is more effective than other forms of contraceptives, fear of pain related to the insertion process is one of the most significant barriers to the use of an IUD among women. Most studies identified pharmacological methods of pain management for IUD insertion, highlighting a need for more research on non-pharmacological methods to improve patient experiences and reduce associated fears.

A novel surface marker CD49d promotes TNF expression in oyster agranulocytes by mediating the MAPK pathway.

CD49d, encoded by the gene Integrin α4, is a significant member of cell adhesion receptors, which is widely expressed in various immune cells to trigger immune responses against invading pathogens. In the present study, the expression of CgCD49d and its regulatory role in TNF expression were investigated in the Pacific oyster Crassostrea gigas. There were five Int-alpha domains, an Integrin_alpha2 region and a unique FG-GAP repeat region inserted identified in CgCD49d. CgCD49d transcript was specifically expressed in haemocytes, and its mRNA expression level in haemocytes increased after LPS and Vibrio splendidus stimulation. After CgCD49d was blocked by using its antibody, the phosphorylation level of CgJNK in the MAPK signaling pathway and CgTNF transcripts decreased significantly post V. splendidus stimulation. After phosphorylation level of CgJNK was inhibited by using its inhibitor, the nuclear translocation of CgRel was restrained and CgTNF transcripts also decreased significantly post V. splendidus stimulation. Furthermore, CgCD49d was found to be mainly expressed in the agranulocyte subpopulation, and Alexa Fluor 488-conjugated CgCD49d antibody labeled agranulocytes with a circle of green fluorescence signals on CgCD49d+ agranulocyte surface under Confocal microscopy, which accounted for 24.9 ± 4.53% of total haemocytes. Collectively, these results suggested that CgCD49d promoted TNF expression in oyster haemocytes against bacterial invasion by mediating MAPK pathway, and it could be used as a surface marker to type and sort a subset of agranulocyte subpopulation among haemocytes.

The impact of the Covid-19 pandemic on the effectiveness of psychosomatic rehabilitation in Germany.

BACKGROUND: The aim of the present study is to investigate the impact of the Covid-19 pandemic on the effectiveness of psychosomatic rehabilitation. METHODS: Between April 2019 and March 2022, a total of 18,388 patients from 7 rehabilitation centres could be included in the study. For each patient, score values from the HEALTH-49 and ICF AT-50 Psych questionnaires were calculated at the beginning and at the end of rehabilitation and the effectiveness of the rehabilitation program was determined by comparing the scores at the beginning and at the end of the rehabilitation programme. Using risk adjusted linear mixed models, three time intervals were compared: a pre-pandemic episode (April 2019 to March 2020), the first year of the pandemic (April 2020 to March 2021) and the second year of the pandemic (April 2021 to March 2022). RESULTS: Overall, it can be stated that the pandemic has substantially impaired the effectiveness of psychosomatic rehabilitation measures. This phenomenon can be observed across a wide range of psychosocial markers and even two years after the start of the pandemic there is no end to the limited effectiveness. With regard to 'psychological and somatoform disorders', for example, there was a relative decrease in the effectiveness of the rehabilitation measure by 11.29% in the first year of the pandemic compared to the pre-pandemic episode, p < 0.001. In the second year of the pandemic, the effectiveness of the rehabilitation measure was still decreased by 8.8% compared to the pre-pandemic episode, p < 0.001. In addition, the evaluations show that a division of the pandemic effect into direct effects (on the individual) and indirect effects (via further complication of the occupational problem environment) can be made and that the pandemic-related complication of the occupational problem environment are still prevalent more than two years after the start of the pandemic. DISCUSSION: The Covid-19 pandemic has had a significant impact on the psychosomatic rehabilitation programs reducing the effectiveness of treatment not only for a short period of time but constantly until March 2022. TRIAL REGISTRATION NUMBER: DRKS00029669; Date of registration: 02/08/2022.

How kelch domain-containing protein 3 distinguishes between the C-end degron of herpesviral protein UL49.5 and its mutants - Insights from molecular dynamics.

The C-terminal residues of proteins can function as degrons recognized by ubiquitin ligases for proteasomal degradation. Kelch domain-containing protein 3 (KLHDC3) is a substrate receptor for E3 ubiquitin ligase (Cullin2-RING ligase) that targets the C-terminal degrons. UL49.5 is 96 amino-acid type 1 transmembrane protein from bovine herpesvirus 1. Herpesviruses have evolved highly effective strategies to evade the antiviral immune response. One of these strategies is inhibition of the antigen processing and presentation pathway by MHC I, thereby reducing the presentation of the antigenic peptides on the surface of the infected cell. Recently, it has been demonstrated that UL49.5 triggers TAP degradation via recruiting the E3 ubiquitin ligase to TAP. Moreover, the mutagenesis revealed that the mutations within the UL49.5 C-degron sequence (93RGRG96) affect binding of UL49.5 to KLHDC3. In this work the molecular dynamics of KLHDC3 in complexes with the C-terminal decapeptide of the herpesviral protein UL4.95 and its three mutants has been employed to provide a framework for understanding molecular recognition of UL49.5 by KLHDC3. The findings of this study give insights into the interactions of the various degrons with KLHDC3. During the molecular dynamics, an active RGKG mutant adopts a conformation similar to that of the wild type decapeptide, whereas the conformations of two inactive mutants, KGRG and RGRD are significantly different. Both R93K and G96D mutations impair the interactions of the C-terminal glycine with KLHDC3. The findings of this study expand the existing knowledge about the mechanism of protein recognition by Cullin2-RING ligases thus contributing to the design of antiviral and anticancer drugs that can selectively promote or inhibit degradation of the proteins of interest.