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Marine spatial planning is a relatively new area of cooperation in the Baltic Sea region — a site of long-term joint efforts towards environmental protection and sustainable development. At the beginning of the 21st century, the integrated management of coastal zones and marine spatial planning emerged as a new area of international cooperation. Despite intensive theoretical work on the mentioned concepts, the development of a harmonised spatial planning in the Baltic Sea region is complicated by the complex nature of the problem, a relatively intensive exploitation of marine resources, diverse interests of the stakeholders, and differences in national institutional systems. We describe the key stages of the process, which is regulated by the EU standards on the one hand and affected by the activity of such organisations as VASAB and HELCOM, on the other. In this article, we examine basic documents defining the principles and scope of marine planning and analyse recent research works into spatial development. We conclude that marine spatial planning is a principal tool of the EU’s integrated policy. Many European countries of the Baltic region are seeking cooperation with Russia to preserve the natural and economic environment of the Baltic Sea. Most joint spatial planning projects have been initiated by Finland, Sweden, Germany, and Poland.

Small Wind Turbines (SWTs) are an increasingly developing Renewable Energy Source, thanks to the gradual popularisation of the prosumer energy generation approach. This, however, requires maximum safety of the machine, working next to households. Reliability is also necessary from the financial point of view, as SWTs should withstand 20 - 30 years of operation without any serious failure to ensure investment profitability. The weakest SWT element is arguably its most exposed one - the rotor - hence the important role played by the blade strength tests. The experimental analysis becomes preferable with increasing popularity of new materials (composites) and production techniques (additive manufacturing). This paper sets out to develop a test stand for static strength examination of 3D-printed SWT blades. This kind of objects is often considered as more vulnerable to structural failures than those created via machining techniques, due to their anisotropic structure, so ensuring structural integrity is crucial for safety reasons.

Baltic integration studies, though dispersed and involving researchers of various disciplines, generally fit well in the field of economic geography research. This article attempts to review the study results of research conducted in Poland in the last four decades. It identifies eleven leading issues, including: the Baltic wide cooperation (conditions and factors, progress and collaboration perspectives), the development of the maritime economy, international legislation, environmental protection, spatial planning and cross-border cooperation. The research focus evolved reflecting the major milestones in geopolitical transformations. In Baltic Europe we can identify three evolutionary phases: identification of cooperation paths and conditions in the competitive environment of two political and military blocks, a recast of options in the period of political transformation and European integration, studies of EU enlargement consequences.

Seaports operate on a highly competitive global transport market. To retain its competitive position a port (terminal) must strengthen its competitive advantages in all fields of activity. Ports are to expand and modernize their infrastructure and superstructure, and develop links with the hinterland and the foreland. The article describes how the port of Gdynia manages to meet these challenges. The author analyses the period 2007—2015. Special attention is paid to the port development plan for 2020. The EU Structural Funds has provided a good opportunity to strengthen the competitive position of the port by making investments in the port infrastructure and superstructure. It allowed the port to strengthen its links with the hinterland. The author uses a set of fundamental, analytical and technical research methods to analyse materials provided by the port authority and the port terminal operators. By the end of 2015, the port authority had completed five investment projects, including the modernization of th ree wharfs and a rail terminal, the development of the port infrastructure aimed to provide services to ro-ro ships. Strategically important projects for the coming years include dredging and widening of the port channel, fairways and the internal basin. Cooperation between the port and the city authorities allowed the port administration to improve road access to the port of Gdynia. The key investment project aims to link the port of Gdynia to the TriCity ring road. Apart from it, there are plans to improve access to the railroad network. Railway line 201 to Bydgoszcz is to be modernised to transport cargoes from Gdynia further inland. The current and future strategic investments create conditions for growth in handling both container and other types of cargo in the port of Gdynia and significantly improve competitiveness of the maritime sector.

Increasing popularity of individualised electricity generation from wind by prosumers creates a strong demand for profitable and highly efficient small wind turbines. This paper investigates the influence of rotor blade solidity parameter on device efficiency in hope of determining its optimal value as a part of the development process of the GUST small wind turbine. The study involved experimental analysis in the wind tunnel and numerical simulations performed in QBlade software. Different solidities of the rotor were achieved by alteration of (1) number of blades and (2) chord distribution along the blade span. The increase of rotor solidity resulted in augmentation of the aerodynamic efficiency in both approaches. The elongation of the chord by 33% in a 3-bladed rotor resulted in a bigger power coefficient increment than addition of a 4th blade with original chord distribution. Even though the solidity was the same, the 3-bladed rotor performed better, possibly due to lower form drag. The results emphasize the importance of the rotor solidity optimization during the small wind turbine rotor development and may significantly influence overall power output.

Antibodies are a cornerstone of the immune system, playing a pivotal role in identifying and neutralizing infections caused by bacteria, viruses, and other pathogens. Understanding their structure, and function, can provide insights into both the body's natural defenses and the principles behind many therapeutic interventions, including vaccines and antibody-based drugs. The analysis and annotation of antibody sequences, including the identification of variable, diversity, joining, and constant genes, as well as the delineation of framework regions and complementarity-determining regions, is essential for understanding their structure and function. Currently analyzing large volumes of antibody sequences is routine in antibody discovery, requiring fast and accurate tools. While there are existing tools designed for the annotation and numbering of antibody sequences, they often have limitations such as being restricted to either nucleotide or amino acid sequences; slow execution times; or reliance on germline databases that are closed, frequently changed, or have sparse coverage for some species. Here, we present the Rapid Immunoglobulin Overview Tool (RIOT), a novel open-source solution for antibody numbering that addresses these shortcomings. RIOT handles nucleotide and amino acid sequence processing, comes integrated with an Open Germline Receptor Database, and is computationally efficient. We hope that the tool will facilitate rapid annotation of antibody sequencing outputs for the benefit of understanding antibody biology and discovering novel therapeutics., (© The Author(s) 2024. Published by Oxford University Press.)

Antibodies are proteins produced by our immune system that have been harnessed as biotherapeutics. The discovery of antibody-based therapeutics relies on analyzing large volumes of diverse sequences coming from phage display or animal immunizations. Identification of suitable therapeutic candidates is achieved by grouping the sequences by their similarity and subsequent selection of a diverse set of antibodies for further tests. Such groupings are typically created using sequence-similarity measures alone. Maximizing diversity in selected candidates is crucial to reducing the number of tests of molecules with near-identical properties. With the advances in structural modeling and machine learning, antibodies can now be grouped across other diversity dimensions, such as predicted paratopes or three-dimensional structures. Here we benchmarked antibody grouping methods using clonotype, sequence, paratope prediction, structure prediction, and embedding information. The results were benchmarked on two tasks: binder detection and epitope mapping. We demonstrate that on binder detection no method appears to outperform the others, while on epitope mapping, clonotype, paratope, and embedding clusterings are top performers. Most importantly, all the methods propose orthogonal groupings, offering more diverse pools of candidates when using multiple methods than any single method alone. To facilitate exploring the diversity of antibodies using different methods, we have created an online tool-CLAP-available at (clap.naturalantibody.com) that allows users to group, contrast, and visualize antibodies using the different grouping methods., Competing Interests: Authors DC, JK, SW, TS, PD, BJ, MT, PD, TG, KK were employed by company NaturalAntibody. Authors AK, MO, TK were employed by company Pure Biologics. Author LS was employed by Boehringer Ingelheim Pharma GmbH & Co. KG. Authors KM and SC were employed by Boehringer Ingelheim., (Copyright © 2024 Chomicz, Kończak, Wróbel, Satława, Dudzic, Janusz, Tarkowski, Deszyński, Gawłowski, Kostyn, Orłowski, Klaus, Schulte, Martin, Comeau and Krawczyk.)

Purpose: Besides the well-established efficacy in preventing severe COVID-19, the impact of early treatments, namely antivirals and monoclonal antibodies (mAbs), on the time length to negativization of SARS-CoV-2 nasal swabs is still unclear. The aim of this study was to compare the efficacy of different early treatments in reducing the SARS-CoV-2 viral shedding, identifying a single drug that might potentially lead to a more rapid negativization of SARS-CoV-2 nasal swab., Methods: This was a single-centre, retrospective, observational study conducted at Ospedale Luigi Sacco in Milan. Data of high-risk COVID-19 patients who received early treatments between 23 December 2021 and March 2023 were extracted. The comparison across treatments was conducted using the Kruskall-Wallis test for continuous variables. Dunn's test with Bonferroni adjustment was performed for post-hoc comparisons of days to negativization. Secondly, a negative binomial regression adjusted for age, sex, number of comorbidities, immunosuppression, and SARS-CoV-2 vaccination status was implemented., Results: Data from 428 patients receiving early treatments were collected. The majority were treated with Nirmatrelvir/Ritonavir and were affected by SARS-CoV-2 Omicron infection with BA.2 sublineage. The median length time to SARS-CoV-2 nasal swab negativization was 9 days [IQR 7-13 days]. We found that Nirmatrelvir/Ritonavir determined a significant decrease of the length time to SARS-CoV-2 nasal swab negativization compared to mAbs (p = 0.003), but not compared to Remdesivir (p = 0.147) and Molnupiravir (p = 0.156)., Conclusion: Our findings highlight the importance of promptly treating high-risk COVID-19 patients with Nirmatrelvir/Ritonavir, as it also contributes to achieving a faster time to negative SARS-CoV-2 nasal swabs., (© 2024. The Author(s).)

Antibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major sources of data (therapeutics, patents, GenBank, literature, and next-generation sequencing outputs), we find that almost all antibodies contain an average of 3-4 such liability motifs in their paratopes, irrespective of the source dataset. This is in line with the common wisdom that liability motif annotation is over-predictive. Therefore, we have compiled three computational flags to prioritize liability motifs for removal from lead drug candidates: 1. germline, to reflect naturally occurring motifs, 2. therapeutic, reflecting chemical liability motifs found in therapeutic antibodies, and 3. surface, indicative of structural accessibility for chemical modification. We show that these flags annotate approximately 60% of liability motifs as benign, that is, the flagged liabilities have a smaller probability of undergoing degradation as benchmarked on two experimental datasets covering deamidation, isomerization, and oxidation. We combined the liability detection and flags into a tool called Liability Antibody Profiler (LAP), publicly available at lap.naturalantibody.com. We anticipate that LAP will save time and effort in de-risking therapeutic molecules., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TS, SW, PD, TG are employees of NaturalAntibody. TK, MO, AK are employees of Pure Biologics. AB is an employee of AstraZeneca. SK is an employee of Moderna, Inc. and may hold stocks/stock options in this and other biopharma companies., (Copyright: © 2024 Satława et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants., Competing Interests: R.M., J.B., C.S.-F., I.B., F.M., K.C., N.S., G.L., C.S., E.C., E.A.D.J., J.R.D., N.C., C.H.-D., A.T., A.A., H.W.V., A.L., D.C., and L.Pi. are or were employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.G. is an external scientific consultant to Humabs BioMed SA. The other authors declare no competing interests., (© 2022 The Authors.)

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month timeframe. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both pre- and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.

The study was aimed at assessing the quality of sexual functioning in female patients having undergone surgical treatment for cancer depending on the type of surgery. The prospective cohort consisted of 48 female patients (23 patients with stoma [A2] and 25 patients with maintained continuity of the GI tract [A1]). Study methods included a diagnostic survey and the analysis of medical records of patients. Research tools consisted of a standardized FSFI questionnaire and a proprietary form for evaluation of sociodemographic data. Measurements were performed at threetimepoints: On the day before the surgery (Measurement I) as well as six and 12 months after the surgery (Measurements II and III, respectively). Statistically significant differences in results were observed in Measurements II and III in the subscales of arousal (II:p = 0.0068, III:p = 0.0018), lubrication (II:p = 0.0221, III:p = 0.0134), orgasm (II:p = 0.0044, III:p = 0.0021), satisfaction (II:p = 0.0021, III:p = 0.0433), and pain/discomfort (II:p = 0.0343, III:p = 0.0473). In all cases, lower scores corresponding to lower quality of sexual functioning were observed in patients in whom stoma had been performed. Statistically significant differences in sexual functioning were observed at Measurements II and III in each group, with the results being significantly (p > 0.05) worse in patients having undergone Hartmann’s procedure or abdominoperineal resection). Variables significantly affecting self-assessed sexual satisfaction included marital status, age, and modality of neoadjuvant treatment. Restoration of the continuity of the gastrointestinal tract is a chance for better self-assessment of the patient’s quality of life as regards sexual functioning.

Purpose: To compare SARS-CoV-2 antigen-specific antibody production and plasma neutralizing capacity against B.1 wild-type-like strain, and Gamma/P.1 and Delta/B.1.617.2 variants-of-concern, in subjects with different Covid-19 disease and vaccination histories., Methods: Adult subjects were: 1) Unvaccinated/hospitalized for Covid-19; 2) Covid-19-recovered followed by one BNT162b2 vaccine dose; and 3) Covid-19-naïve/2-dose BNT162b2 vaccinated. Multiplex Luminex ® immunoassays measured IgG, IgA, and IgM plasma levels against SARS-CoV-2 receptor-binding domain (RBD), spike-1 (S), and nucleocapsid proteins. Neutralizing activity was determined in Vero E6 cytopathic assays., Results: Maximum anti-RBD IgG levels were similar in Covid - 19‑recovered individuals 8‒10 days after single-dose vaccination and in Covid-19-naïve subjects 7 days after 2 nd vaccine dosing; both groups had ≈2‑fold higher anti-RBD IgG levels than Unvaccinated/Covid-19 subjects tracked through 2 weeks post-symptom onset. Anti-S IgG expression patterns were similar to RBD within each group, but with lower signal strengths. Viral antigen-specific IgA and IgM levels were more variable than IgG patterns. Anti-nucleocapsid immunoglobulins were not detected in Covid-19-naïve subjects. Neutralizing activity against the B.1 strain, and Gamma/P.1 and Delta/B.1.617.2 variants, was highest in Covid‑19-recovered/single-dose vaccinated subjects; although neutralization against the Delta variant in this group was only 26% compared to B.1 neutralization, absolute anti-Delta titers suggested maintained protection. Neutralizing titers against the Gamma and Delta variants were 33‒77% and 26‒67%, respectively, versus neutralization against the B.1 strain (100%) in the three groups., Conclusion: These findings support SARS-CoV-2 mRNA vaccine usefulness regardless of Covid-19 history, and confirm remarkable protection provided by a single vaccine dose in people who have recovered from Covid-19., Competing Interests: WD was an employee of Luminex Corporation during the study period. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tarkowski, de Jager, Schiuma, Covizzi, Lai, Gabrieli, Corbellino, Bergna, Ventura, Galli, Riva and Antinori.)

Disinfection of surfaces by ultraviolet-C (UV-C) radiation is gaining importance in diverse applications. However, there is generally no accepted computational procedure to determine the minimum irradiation times and UV-C doses required for reliable and secure disinfection of surfaces. UV-C dose distributions must be comparable for devices presently on the market and future ones, as well as for the diverse surfaces of objects to be disinfected. A mathematical model is presented to estimate irradiance distributions. To this end, the relevant parameters are defined. These parameters are the optical properties of the UV-C light sources, such as wavelength and emitted optical power, as well as electrical features, like radiant efficiency and consumed power. Furthermore, the characteristics and geometry of the irradiated surfaces as well as the positions of the irradiated surfaces in relation to the UV-C light sources are considered. Because mercury (Hg) lamps are competitive with UV-C light-emitting diodes, a comparative analysis between these two light sources based on the simulation results is also discussed.

Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects. This dysregulation was accompanied by a deficient response of neutrophils to LPS, impaired cytokine/chemokine/growth factor synthesis, and increased apoptosis. Chromatin immunoprecipitation sequencing (ChIPseq) H3K4me3 histone analysis revealed that the most spectacular abnormalities were observed in the exons, introns, and promoter-TSS regions. Bioinformatic analysis of Gene Ontology, including biological processes, molecular function, and cellular components, demonstrated that the main changes were related to the genes responsible for cell activation, cytokine production, adhesive molecule expression, histone remodeling via upregulation of methyltransferase process, and downregulation of NF-κB transcription factor in canonical pathways. Abnormalities within H3K4me3 implicated LPS-mediated NF-κB canonical activation pathway that was a result of low amounts of κB DNA sites within histone H3K4me3, low NF-κB (p65 RelA) and TLR4 mRNA expression, and reduced free NF-κB (p65 RelA) accumulation in the nucleus. Genome-wide survey of H3K4me3 provided evidence that chromatin modifications lead to an impairment within the canonical NF-κB cell activation pathway causing the neutrophil dysfunction observed in HIV-infected individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Piatek, Tarkowski, Namiecinska, Riva, Wieczorek, Michlewska, Dulska, Domowicz, Kulińska-Michalska, Lewkowicz and Lewkowicz.)

Background: The Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The aim of this study was to examine the seroprevalence trends of SARS-CoV-2 in healthy asymptomatic adults, and the risk factors and laboratory correlates of positive tests., Materials and Methods: We conducted a cross-sectional study in a random sample of blood donors, who were asymptomatic at the time of evaluation, at the beginning of the first phase (February 24 th to April 8 th 2020; n=789). Presence of IgM/IgG antibodies against the SARS-CoV-2-Nucleocapsid protein was assessed by a lateral flow immunoassay., Results: The test had a 100/98.3 sensitivity/specificity (n=32/120 positive/negative controls, respectively), and the IgG test was validated in a subset by an independent ELISA against the Spike protein (n=34, p<0.001). At the start of the outbreak, the overall adjusted seroprevalence of SARS-CoV-2 was 2.7% (95% CI: 0.3-6%; p<0.0001 vs 120 historical controls). During the study period, characterised by a gradual implementation of social distancing measures, there was a progressive increase in the adjusted seroprevalence to 5.2% (95% CI: 2.4-9.0; 4.5%, 95% CI: 0.9-9.2% according to a Bayesian estimate) due to a rise in IgG reactivity to 5% (95% CI: 2.8-8.2; p=0.004 for trend), but there was no increase in IgM + (p=not significant). At multivariate logistic regression analysis, IgG reactivity was more frequent in younger individuals (p=0.043), while IgM reactivity was more frequent in individuals aged >45 years (p=0.002)., Discussion: SARS-CoV-2 infection was already circulating in Milan at the start of the outbreak. The pattern of IgM/IgG reactivity was influenced by age: IgM was more frequently detected in participants aged >45 years. By the end of April, 2.4-9.0% of healthy adults had evidence of seroconversion.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics., Competing Interests: Declaration of Interests L.P., N.C., M. Beltramello, C.S.-F., D.P., L.E.R., F.Z., N.S., J.B., A.P., S. Jaconi, B.G., A.M., A.D.M., M.S.P., E.C., S.V.G., F.J., C.H.-D., M.S., D.H., G.S., K.F., H.W.V., A.L., and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d + CD154 + lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d + CD154 + lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d + CD154 + lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d + CD154 + lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d + CD154 + cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG 3 5 - 55 ) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d + /CD154 + cells were found to be co-localized with O4 + cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d + CD154 + lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment., Competing Interests: The authors declare no conflict of interest.

The critical aspect in multiple sclerosis (MS) progression involves insufficient regeneration of CNS resulting from deficient myelin synthesis by newly generated oligodendrocytes (OLs). Although many studies have focused on the role of autoreactive lymphocytes in the inflammatory-induced axonal loss, the problem of insufficient remyelination and disease progression is still unsolved. To determine the effect of myelin-specific lymphocytes on OL function in MS patients and in a mouse model of MS, we cultured myelin induced MS CD49d + CD154 + circulating lymphocytes as well as Experimental Autoimmune Encephalomyelitis (EAE) mouse brain-derived T and memory B cells with maturing oligodendrocyte precursor cells (OPCs). We found that myelin-specific CD49d + CD154 + lymphocytes affected OPC maturation toward formation of immune reactive OLs. Newly generated OLs were characterized by imbalanced myelin basic protein (MBP) and proteolipid protein (PLP) production as well as proinflammatory chemokine/cytokine synthesis. The analysis of cellular pathways responsible for OL reprogramming revealed that CD49d + CD154 + lymphocytes affected miRNA synthesis by dysregulation of polymerase II activity. miR-665 and ELL3 turned out to be the main targets of MS myelin-specific lymphocytes. Neutralization of high intracellular miR-665 concentration restored miRNA and MBP/PLP synthesis. Together, these data point to new targets for therapeutic intervention promoting CNS remyelination.

Potent and broadly neutralizing antibodies (bnAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is targeted by the most broadly reactive HIV-1 neutralizing antibodies. Here, we examine the structural and molecular mechansims of neutralization by anti-MPER bnAb, LN01, which was isolated from lymph-node-derived germinal center B cells of an elite controller and exhibits broad neutralization breadth. LN01 engages both MPER and the transmembrane (TM) region, which together form a continuous helix in complex with LN01. The tilted TM orientation allows LN01 to interact simultaneously with the peptidic component of the MPER epitope and membrane via two specific lipid binding sites of the antibody paratope. Although LN01 carries a high load of somatic mutations, most key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia.

In normal and tumor cells, polyunsaturated fatty acids (PUFAs) act as intracellular second messengers, which play a role in signaling, proliferation and cell death. PUFAs have selective tumoricidal action and may alter sensitivity of tumor cells to cisplatin (CDDP), a commonly used anticancer agent. The aim of this study was to evaluate the influence of arachidonic acid (AA, 20:4 n-6), eicosapentaenoic acid (EPA, 20:5 n-3), docosahexaenoic acid (DHA, 22:6 n-3) and CDDP on autophagy and apoptosis in A549 human lung adenocarcinoma cells. Viability of A549 cells treated with CDDP and PUFAs was measured using the XTT tetrazolium salt based assay. Caspase-3/7 activity was estimated using ApoTox-Glo kit (Promega). Autophagic vac- uoles were detected by Cyto-ID Autophagy Detection Kit (Enzo). The results were compared to control cultures maintained in the absence of CDDP and PUFAs. PUFAs, in particular EPA and DHA, added to the cultivation medium, increased the antitumor activity of CDDP in A549 cells in a concentration dependent manner. In case of AA this effect was observed at the highest of the concentrations tested only (100 μM). Both, EPA and DHA, but not AA, significantly increased the amount of autophagic vacuoles and induced caspase-3/7 activity. The obtained results suggest that the antiproliferative effect of CDDP in A549 cells can be enhanced by AA and in particular by EPA and DHA through their influence on autophagic and apoptotic cell death. It is likely that BPA and DHA incorporated to the tumor cells may improve outcomes in lung cancer patients.

The objective of the study was to characterize better the immunologic mechanisms underlying a previously developed animal model of chemical-induced asthma. BALB/c and severe combined immunodeficiency disease (SCID) mice received toluene diisocyanate (TDI) or vehicle on each ear on day 1 and/or day 7. On day 10, they were intranasally challenged with TDI or vehicle. Ventilatory function was monitored by whole body plethysmography for 40 min after challenge. Reactivity to methacholine was measured 23 h later: enhanced pause and actual resistance measurements. Pulmonary inflammation was assessed 1, 6, and 24 h after challenge by bronchoalveolar lavage (BAL). Tumor necrosis factor-alpha and macrophage inflammatory protein (MIP)-2 levels were measured in BAL. Immunological parameters included total IgE, IgG1, and IgG2a in serum, lymphocyte populations in auricular and cervical lymph nodes, and IL-4 and IFN-gamma levels in supernatants of lymph node cells, cultured with or without concanavalin A. Ventilatory changes suggestive of airway obstruction and increased methacholine reactivity were observed in all TDI-sensitized and TDI intranasally instilled mice, except in SCID mice. A neutrophil influx, accompanied by an increase in MIP-2 levels, was found in BAL of all responding groups 6 and 24 h after intranasal challenge. In BALB/c mice an increased level of CD19+ B cells was found in the auricular lymph nodes. IL-4 and IFN-gamma levels were increased in supernatants of concanavalin A-stimulated auricular lymph node cells from BALB/c mice completely treated with TDI. These results indicate that our model is dependent on the presence of lymphocytes, but it is not characterized by a preferential stimulation of Th1 or Th2 lymphocytes.

The alpha4 chain (CD49d), which constitutes one of the chains of alpha4beta1 (very late activating antigen-4 [VLA-4]) and alpha4beta7 integrins, mediates migration of T cells to extravascular spaces. The interaction between VLA-4 and vascular cell adhesion molecule-1 (VCAM-1) has been shown to be the critical pathway for the selective accumulation of eosinophils and basophils at sites of allergic inflammation. T lymphocytes are also specifically recruited into allergic sites, including the allergic asthmatic airway. Increased numbers of activated CD4+ cells expressing the DR antigen subset of the human leukocyte antigens (HLA-DR) appear in the allergic lung 48 h after allergen inhalation. The mechanisms by which these cells localize into the lung are still unknown. We report that stimulation of allergen-specific T cells with allergen in vitro resulted in enhanced expression of alpha4 chain (CD49d) as measured by receptor density on allergen-specific T-cell lines and T-cell clones. Kinetic studies showed that CD49d density was enhanced over a 24- to 48-h period in a time-dependent fashion, and was coordinately upregulated with HLA-DR expression. We also demonstrated that increased expression of CD49d on T-cell lines 24 h and 48 h after stimulation correlated with increased adhesion to the CS-1 fragment of fibronectin. In contrast, lymphocyte function-associated antigen-1b (LFA-1b) (CD11b), LFA-3 (CD58), and intercellular adhesion molecule-1 (ICAM-1) (CD54) expression did not change with allergen stimulation. We also showed that CD49d receptor density on T cells obtained by bronchoalveolar lavage (BAL) of allergic patients before and 48 h after allergen challenge was significantly higher than that on T cells taken from BAL of normal subjects and from controls with other inflammatory lung diseases. Taken together, these findings indicate that allergen stimulation activates allergen-specific T cells and coordinately induces increased CD49d receptor expression and binding to counterligands. We postulate that allergen-driven upregulation of CD49d, which together with the beta1 chain constitutes VLA-4 integrin, may be responsible for the selective accumulation of T cells in the allergic asthmatic lung.