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1.
Front Immunol ; 15: 1388721, 2024.
Article in English | MEDLINE | ID: mdl-38840926

ABSTRACT

The disaccharide (ß-D-glucopyranosyluronic acid)-(1→4)-ß-D-glucopyranoside represents a repeating unit of the capsular polysaccharide of Streptococcus pneumoniae serotype 3. A conjugate of the disaccharide with BSA (di-BSA conjugate) adjuvanted with aluminum hydroxide induced - in contrast to the non-adjuvanted conjugate - IgG1 antibody production and protected mice against S. pneumoniae serotype 3 infection after intraperitoneal prime-boost immunization. Adjuvanted and non-adjuvanted conjugates induced production of Th1 (IFNγ, TNFα); Th2 (IL-5, IL-13); Th17 (IL-17A), Th1/Th17 (IL-22), and Th2/Th17 cytokines (IL-21) after immunization. The concentration of cytokines in mice sera was higher in response to the adjuvanted conjugate, with the highest level of IL-17A production after the prime and boost immunizations. In contrast, the non-adjuvanted conjugate elicited only weak production of IL-17A, which gradually decreased after the second immunization. After boost immunization of mice with the adjuvanted di-BSA conjugate, there was a significant increase in the number of CD45+/CD19+ B cells, TCR+ γδ T cell, CD5+ В1 cells, and activated cells with MHC II+ expression in the spleens of the mice. IL-17A, TCR+ γδ T cells, and CD5+ В1 cells play a crucial role in preventing pneumococcal infection, but can also contribute to autoimmune diseases. Immunization with the adjuvanted and non-adjuvanted di-BSA conjugate did not elicit autoantibodies against double-stranded DNA targeting cell nuclei in mice. Thus, the molecular and cellular markers associated with antibody production and protective activity in response to immunization with the di-BSA conjugate adjuvanted with aluminum hydroxide are IL-17A, TCR+ γδ T cells, and CD5+ В1 cells against the background of increasing MHC II+ expression.


Subject(s)
Interleukin-17 , Pneumococcal Vaccines , Serum Albumin, Bovine , Streptococcus pneumoniae , Animals , Interleukin-17/immunology , Interleukin-17/metabolism , Streptococcus pneumoniae/immunology , Mice , Serum Albumin, Bovine/immunology , Pneumococcal Vaccines/immunology , Pneumococcal Infections/immunology , Pneumococcal Infections/prevention & control , Disaccharides/immunology , Bacterial Capsules/immunology , Polysaccharides, Bacterial/immunology , Adjuvants, Immunologic/administration & dosage , Female , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Intraepithelial Lymphocytes/immunology , Serogroup , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism
2.
ACS Sustain Resour Manag ; 1(5): 842-856, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38807756

ABSTRACT

This study establishes a foundation for the ionic liquid (IL) pretreatment of duckweed biomass. An optimized IL-based process was designed to exploit the unique properties of duckweed including efficient metal removal, potential starch accumulation, and protein accumulation. Two ILs, namely, dimethylethanolammonium formate ([DMEtA][HCOO]) and N,N-dimethylbutylammonium hydrogen sulfate ([DMBA][HSO4]), were investigated for the pretreatment of two duckweed species (Spirodela polyrhiza and Lemna minor). The evaluation focused on starch recovery, sugar release, protein recovery, and metal extraction capabilities. [DMEtA][HCOO] demonstrated near-quantitative starch recoveries at 120 °C, while [DMBA][HSO4] showed similar performance at 90 °C within a reaction time of 2 h. Saccharification yields for most pulps exceeded 90% after 8 h of hydrolysis, outperforming "traditional" lignocellulosic biomasses such as miscanthus or sugarcane bagasse. Approximately 50 and 80 wt % of the protein were solubilized in [DMEtA][HCOO] and [DMBA][HSO4], respectively, while the remaining protein distributed between the pulp and lignin. However, the solubilized protein in the IL could not be recovered due to its low molecular weight. Regarding metal extraction, [DMEtA][HCOO] demonstrated higher efficiency, achieving 81% removal of Ni from Lemna minor's pulps, whereas [DMBA][HSO4] extracted only 28% of Ni with slightly higher pulp concentrations. These findings indicate the need for further optimization in concurrent metal extraction using ILs.

3.
BMC Health Serv Res ; 24(1): 294, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38448939

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, provision of non-COVID healthcare was recurrently severely disrupted. The objective was to determine whether disruption of non-COVID hospital use, either due to cancelled, postponed, or forgone care, during the first pandemic year of COVID-19 impacted socioeconomic groups differently compared with pre-pandemic use. METHODS: National population registry data, individually linked with data of non-COVID hospital use in the Netherlands (2017-2020). in non-institutionalised population of 25-79 years, in standardised household income deciles (1 = low, 10 = high) as proxy for socioeconomic status. Generic outcome measures included patients who received hospital care (dichotomous): outpatient contact, day treatment, inpatient clinic, and surgery. Specific procedures were included as examples of frequently performed elective and acute procedures, e.g.: elective knee/hip replacement and cataract surgery, and acute percutaneous coronary interventions (PCI). Relative risks (RR) for hospital use were reported as outcomes from generalised linear regression models (binomial) with log-link. An interaction term was included to assess whether income differences in hospital use during the pandemic deviated from pre-pandemic use. RESULTS: Hospital use rates declined in 2020 across all income groups. With baseline (2019) higher hospital use rates among lower than higher income groups, relatively stronger declines were found for lower income groups. The lowest income groups experienced a 10% larger decline in surgery received than the highest income group (RR 0.90, 95% CI 0.87 - 0.93). Patterns were similar for inpatient clinic, elective knee/hip replacement and cataract surgery. We found small or no significant income differences for outpatient clinic, day treatment, and acute PCI. CONCLUSIONS: Disruption of non-COVID hospital use in 2020 was substantial across all income groups during the acute phases of the pandemic, but relatively stronger for lower income groups than could be expected compared with pre-pandemic hospital use. Although the pandemic's impact on the health system was unprecedented, healthcare service shortages are here to stay. It is therefore pivotal to realise that lower income groups may be at risk for underuse in times of scarcity.


Subject(s)
COVID-19 , Cataract , Percutaneous Coronary Intervention , Humans , COVID-19/epidemiology , Pandemics , Poverty , Ambulatory Care Facilities , Hospitals
4.
J Phys Chem Lett ; 15(9): 2311-2318, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38386631

ABSTRACT

In this paper, we investigated the effect of cation structure and water content on proton dissociation in alkylammonium [HSO4]- protic ionic liquids (ILs) doped with 20 wt % water and correlated this with experimental Hammett acidities. For pure systems, increased cation substitution resulted in a reduction in the number of direct anion-anion neighbors leading to larger numbers of small aggregates, which is further enhanced with addition of water. We also observed spontaneous proton dissociation from [HSO4]- to water only for primary amine-based protic ILs, preceded by the formation of an anion trimer motif. Investigation using DFT calculations revealed spontaneous proton dissociation from [HSO4]- to water can occur for each of the protic ILs investigated; however, this is dependent on the size of the anion aggregates. These findings are important in the fields of catalysis and lignocellulosic biomass, where solvent acidity is a crucial parameter in biomass fractionation and lignin chemistry.

5.
Health Promot Int ; 39(1)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38381914

ABSTRACT

Local governments may play a key role in making outdoor sports clubs smoke free. This study aims to assess the activities, motives, challenges and strategies of Dutch municipalities regarding stimulating outdoor sports clubs to become smoke free. Semi-structured interviews were conducted with 19 policy officers of different municipalities in the Netherlands. The included municipalities varied in terms of region, population size and degree of urbanization. Data were analyzed using content analysis. Municipalities stimulated sports clubs to become smoke free by providing information and support and, to a lesser extent, by using financial incentives. Motives of municipalities varied from facilitating a healthy living environment for youth, responding to denormalization of smoking and aligning with goals formulated in national prevention policy. Policy officers faced several challenges, including limited capacity and funds, a reluctance to interfere with sports clubs and little support within the municipal organization. These challenges were addressed by employing various strategies such as embedding smoke-free sports in a broader preventive policy, setting a good example by creating outdoor smoke-free areas around municipal buildings, and collaborating with stakeholders in the municipality to join forces in realizing smoke-free sports clubs. Municipalities demonstrated evident motivation to contribute to a smoke-free sports environment. Currently, most municipalities fulfil an informative and supportive role, while some municipalities still explore their role and position in relation to supporting sports clubs to become smoke free. Other municipalities have established, according to them, effective strategies.


Subject(s)
Smoke-Free Policy , Sports , Adolescent , Humans , Cities , Health Policy , Ethnicity
6.
Pharmaceutics ; 16(1)2024 Jan 18.
Article in English | MEDLINE | ID: mdl-38258135

ABSTRACT

In this study, we described physico-chemical properties of novel nanoformulation of photosensitizer-pyropheophorbide α 17-diethylene glycol ester (XL) (chlorophyll α derivative), revealing insights into antitumor activity and maintaining quality, meeting the pharmaceutical approach of new nanoformulation design. Our formulation, based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles, increased XL solubility and selective tumor-targeted accumulation. In our research, we revealed, for the first time, that XL binding to polyvinyl alcohol (PVA) enhances XL photophysical activity, providing the rationale for PVA application as a stabilizer for nanoformulations. Results of FTIR, DSC, and XRD revealed the physical interactions between XL and excipients, including PVA, indicating that the encapsulation maintained XL binding to PVA. The encapsulated XL exhibited higher photophysical activity compared to non-encapsulated substance, which can be attributed to the influence of residual PVA. Gamma-irradiation led to degradation of XL; however, successful sterilization of the samples was achieved through the filtration. Importantly, the encapsulated and sterilized XL retained cytotoxicity against both 2D and 3D tumor cell models, demonstrating the potential of the formulated NP-XL for photodynamic therapy applications, but lacked the ability to reactivate epigenetically silenced genes. These findings provide valuable insights into the design and characterization of PLGA-based nanoparticles for the encapsulation of photosensitizers.

7.
Nicotine Tob Res ; 26(7): 922-930, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38195238

ABSTRACT

INTRODUCTION: Social and Community Service Organizations (SCSOs) are a potential setting to reach and support people with a low socioeconomic position who smoke, yet smoking cessation is not widely supported by SCSO professionals. AIMS AND METHODS: This study aims to identify SCSO professionals' (1) potential activities to support smoking cessation and (2) barriers and facilitators in undertaking these activities. Between July and November 2022, semi-structured interviews were conducted with 21 professionals recruited through SCSOs in Amsterdam North, including participation workers, welfare workers, parent and child counselors, budget coach, debt counselor, welfare work, community sports, and community center coordinators. Data were analyzed using a thematic approach. RESULTS: Eight activities were identified that could support the client either directly (ie, recognizing smoking clients, discussing smoking and smoking cessation, referring clients, providing smoking cessation counseling, offering help around services) or indirectly (ie, collaboration with relevant network partners, implementing smoke-free environments, enhancing professional skills). Various barriers and facilitators were identified related to the (1) client and their environment (ie, clients' readiness and social environment), (2) interaction between professional and client (ie, topic sensitivity), (3) professional (ie, professional is non-smoker, knowledge, and self-efficacy), (4) professionals' work environment (ie, necessity, responsibility, priority, and time), and (5) smoking cessation services (ie, availability of appropriate services and referral process). CONCLUSIONS: There is potential for SCSO professionals to support smoking cessation, but several barriers hinder their efforts. To address these barriers, it is essential to take into account the factors that SCSO professionals believe facilitate the provision of smoking cessation support. IMPLICATIONS: This study provides insight into how the potential of SCSOs in Amsterdam North to support smoking cessation efforts among people with a low socioeconomic position can be harnessed. Barriers were found at multiple levels (client, professional, client-professional interaction, and organizational) and these findings imply that stakeholders across these levels will need to prioritize smoking cessation to facilitate and stimulate SCSO professionals in supporting smoking cessation. A concrete action would be to offer SCSO professionals additional training in conversational skills to discuss smoking. As a prerequisite, easily accessible and suitable smoking cessation services should be available in the neighborhood.


Subject(s)
Smoking Cessation , Humans , Smoking Cessation/methods , Smoking Cessation/psychology , Female , Male , Counseling/methods , Adult , Middle Aged , Netherlands , Community Health Services , Social Work
8.
Photochem Photobiol Sci ; 23(1): 177-187, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38071235

ABSTRACT

Kinetic and thermodynamic parameters have been investigated for the thermal Z‒E isomerization of dihydroquinolylazotetrazole dyes with alkyl substituents (Me, t-Bu, and Adm) at positions 1 (dyes 2) and 2 (dyes 3) of the tetrazole moiety in two solvents of different polarity, acetonitrile (MeCN) and toluene. The experimental results show crucial dependence of these parameters on a substituent position in the tetrazole moiety and on a solvent. For dyes 2, Eact and ΔH‡ are lower in MeCN than in toluene that results in a high increase in the lifetimes of the Z isomers: from milliseconds in MeCN to minutes in toluene. For dyes 3, the difference in Eact and ΔH‡ in the two solvents is opposite: Eact and ΔH‡ are by more than 20 kJ mol-1 higher in MeCN, nevertheless, the rate constants for 3 in toluene are comparable with those in MeCN at the ambient temperature and the difference in the behavior is determined by the value of negative entropy of activation. Quantum-chemical calculations of the thermal Z‒E isomerization show the possibility of the process to occur via crossing from the S0 to the thermally induced T1 state. The contribution of this path is highest for 3 in toluene. The analysis of the absorption spectra demonstrates that for the E isomers, the n‒π* and π‒π* transitions are within the long-wavelength absorption band and their positions relative each other are opposite in the solvents: the n‒π* transition is blue-shifted relative to the π‒π* transition in MeCN and is red-shifted in toluene.

9.
Neuron ; 112(1): 41-55.e3, 2024 Jan 03.
Article in English | MEDLINE | ID: mdl-37898123

ABSTRACT

Primary cilia act as antenna receivers of environmental signals and enable effective neuronal or glial responses. Disruption of their function is associated with circuit disorders. To understand the signals these cilia receive, we comprehensively mapped cilia's contacts within the human cortical connectome using serial-section EM reconstruction of a 1 mm3 cortical volume, spanning the entire cortical thickness. We mapped the "contactome" of cilia emerging from neurons and astrocytes in every cortical layer. Depending on the layer and cell type, cilia make distinct patterns of contact. Primary cilia display cell-type- and layer-specific variations in size, shape, and microtubule axoneme core, which may affect their signaling competencies. Neuronal cilia are intrinsic components of a subset of cortical synapses and thus a part of the connectome. This diversity in the structure, contactome, and connectome of primary cilia endows each neuron or glial cell with a unique barcode of access to the surrounding neural circuitry.


Subject(s)
Cilia , Connectome , Humans , Neurons/physiology , Cerebral Cortex , Neuroglia/physiology
10.
Sci Rep ; 13(1): 19398, 2023 11 08.
Article in English | MEDLINE | ID: mdl-37938619

ABSTRACT

Staphylococcus aureus forms biofilms that cause considerable morbidity and mortality in patients who receive implanted devices such as prosthetics or fixator pins. An ideal surface for such medical devices would inhibit biofilm growth. Recently, it was reported that surface modification of stainless steel materials with carbon-infiltrated carbon nanotubes (CICNT) inhibits the growth of S. aureus biofilms. The purpose of this study was to investigate this antimicrobial effect on titanium materials with CICNT coated surfaces in a variety of surface morphologies and across a broader spectrum of S. aureus isolates. Study samples of CICNT-coated titanium, and control samples of bare titanium, a common implant material, were exposed to S. aureus. Viable bacteria were removed from adhered biofilms and quantified as colony forming units. Scanning electron microscopy was used to qualitatively analyze biofilms both before and after removal of cells. The CICNT surface was found to have significantly fewer adherent bacteria than bare titanium control surfaces, both via colony forming unit and microscopic analyses. This effect was most pronounced on CICNT surfaces with an average nanotube diameter of 150 nm, showing a 2.5-fold reduction in adherent bacteria. Since S. aureus forms different biofilm structures by isolate and by growth conditions, we tested 7 total isolates and found a significant reduction in the biofilm load in six out of seven S. aureus isolates tested. To examine whether the anti-biofilm effect was due to the structure of the nanotubes, we generated an unstructured carbon surface. Significantly more bacteria adhered to a nonstructured carbon surface than to the 150 nm CICNT surface, suggesting that the topography of the nanotube structure itself has anti-biofilm properties. The CICNT surface possesses anti-biofilm properties that result in fewer adherent S. aureus bacteria. These anti-biofilm properties are consistent across multiple isolates of S. aureus and are affected by nanotube diameter. The experiments performed in this study suggest that this effect is due to the nanostructure of the CICNT surface.


Subject(s)
Nanotubes, Carbon , Humans , Staphylococcus aureus , Titanium/pharmacology , Biofilms , Bone Nails
11.
Front Microbiol ; 14: 1211999, 2023.
Article in English | MEDLINE | ID: mdl-38029097

ABSTRACT

Introduction: Serratia marcescens is most commonly known as an opportunistic pathogen causing nosocomial infections. It, however, was shown to infect a wide range of hosts apart from vertebrates such as insects or plants as well, being either pathogenic or growth-promoting for the latter. Despite being extensively studied in terms of virulence mechanisms during human infections, there has been little evidence of which factors determine S. marcescens host specificity. On that account, we analyzed S. marcescens pangenome to reveal possible specificity factors. Methods: We selected 73 high-quality genome assemblies of complete level and reconstructed the respective pangenome and reference phylogeny based on core genes alignment. To find an optimal pipeline, we tested current pangenomic tools and obtained several phylogenetic inferences. The pangenome was rich in its accessory component and was considered open according to the Heaps' law. We then applied the pangenome-wide associating method (pan-GWAS) and predicted positively associated gene clusters attributed to three host groups, namely, humans, insects, and plants. Results: According to the results, significant factors relating to human infections included transcriptional regulators, lipoproteins, ABC transporters, and membrane proteins. Host preference toward insects, in its turn, was associated with diverse enzymes, such as hydrolases, isochorismatase, and N-acetyltransferase with the latter possibly exerting a neurotoxic effect. Finally, plant infection may be conducted through type VI secretion systems and modulation of plant cell wall synthesis. Interestingly, factors associated with plants also included putative growth-promoting proteins like enzymes performing xenobiotic degradation and releasing ammonium irons. We also identified overrepresented functional annotations within the sets of specificity factors and found that their functional characteristics fell into separate clusters, thus, implying that host adaptation is represented by diverse functional pathways. Finally, we found that mobile genetic elements bore specificity determinants. In particular, prophages were mainly associated with factors related to humans, while genetic islands-with insects and plants, respectively. Discussion: In summary, functional enrichments coupled with pangenomic inferences allowed us to hypothesize that the respective host preference is carried out through distinct molecular mechanisms of virulence. To the best of our knowledge, the presented research is the first to identify specific genomic features of S. marcescens assemblies isolated from different hosts at the pangenomic level.

12.
Biomimetics (Basel) ; 8(6)2023 Oct 14.
Article in English | MEDLINE | ID: mdl-37887618

ABSTRACT

Cardiac arrhythmias are a major cause of cardiovascular mortality worldwide. Many arrhythmias are caused by reentry, a phenomenon where excitation waves circulate in the heart. Optical mapping techniques have revealed the role of reentry in arrhythmia initiation and fibrillation transition, but the underlying biophysical mechanisms are still difficult to investigate in intact hearts. Tissue engineering models of cardiac tissue can mimic the structure and function of native cardiac tissue and enable interactive observation of reentry formation and wave propagation. This review will present various approaches to constructing cardiac tissue models for reentry studies, using the authors' work as examples. The review will highlight the evolution of tissue engineering designs based on different substrates, cell types, and structural parameters. A new approach using polymer materials and cellular reprogramming to create biomimetic cardiac tissues will be introduced. The review will also show how computational modeling of cardiac tissue can complement experimental data and how such models can be applied in the biomimetics of cardiac tissue.

13.
Prev Med ; 177: 107737, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37858735

ABSTRACT

OBJECTIVE: This commentary emphasizes the importance of implementing outdoor smoke-free policies at sports clubs, particularly highlighting their limited adoption across Europe. The primary aim was to assess the progress made in the Netherlands, explore the strategies employed, and outline future challenges. METHODS: Our methodology involved an examination of national regulations and the voluntary adoption of smoke-free policies at sports clubs throughout Europe. We also assessed the adoption and implementation of these policies using recent evidence, leading to the identification of impending challenges in their implementation across Europe. RESULTS: While only a few European countries currently have national legislation prohibiting outdoor smoking at sports clubs, voluntary initiatives promoting such policies have emerged in various nations. Experiences from the Netherlands have demonstrated the feasibility of implementing outdoor smoke-free policies at sports clubs. To expand these policies across Europe, five key challenges need to be addressed: 1) encouraging smoke-free policies at sports clubs that are less inclined to adopt them, 2) ensuring consistent compliance and enforcement of outdoor smoke-free policies, 3) preventing smoking just outside the sports club, 4) garnering support from various stakeholders to ensure widespread adoption of smoke-free sports clubs, and 5) establishing monitoring and evaluation mechanisms for policy implementation. CONCLUSION: The Dutch experiences serve as a testimony to the feasibility of outdoor smoke-free policies at sports clubs. By addressing the remaining challenges, we can create healthier sports environments for children and take substantial steps towards realizing a smoke-free Europe.


Subject(s)
Smoke-Free Policy , Sports , Tobacco Smoke Pollution , Child , Humans , Tobacco Smoke Pollution/prevention & control , Europe , Environment
14.
bioRxiv ; 2023 Sep 21.
Article in English | MEDLINE | ID: mdl-37790363

ABSTRACT

Microglia diversity emerges from interactions between intrinsic genetic programs and environment-derived signals, but how these processes unfold and interact in the developing brain remains unclear. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) expressed in radial glia progenitors activates microglia-expressed TGFß1, permitting microglial development. Domain-restricted deletion of Itgb8 in these progenitors establishes complementary regions with developmentally arrested "dysmature" microglia that persist into adulthood. In the absence of autocrine TGFß1 signaling, we find that microglia adopt a similar dysmature phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the TGFß signal transducers Smad2 and Smad3 have a less polarized dysmature phenotype and correspondingly less severe neuromotor dysfunction. Finally, we show that non-canonical (Smad-independent) signaling partially suppresses disease and development associated gene expression, providing compelling evidence for the adoption of microglial developmental signaling pathways in the context of injury or disease.

16.
Front Bioeng Biotechnol ; 11: 1209472, 2023.
Article in English | MEDLINE | ID: mdl-37840657

ABSTRACT

Background: In vivo measurements of segmental-level kinematics are a promising avenue for better understanding the relationship between pain and its underlying, multi-factorial basis. To date, the bulk of the reported segmental-level motion has been restricted to single plane motions. Methods: The present work implemented a novel marker set used with an optical motion capture system to non-invasively measure dynamic, 3D in vivo segmental kinematics of the lower spine in a laboratory setting. Lumbar spinal kinematics were measured for 28 subjects during 17 diagnostic movements. Results: Overall regional range of motion data and lumbar angular velocity measurement were consistent with previously published studies. Key findings from the work included measurement of differences in ascending versus descending segmental velocities during functional movements and observations of motion coupling paradigms in the lumbar spinal segments. Conclusion: The work contributes to the task of establishing a baseline of segmental lumbar movement patterns in an asymptomatic cohort, which serves as a necessary pre-requisite for identifying pathological and symptomatic deviations from the baseline.

17.
J Lipid Res ; 64(11): 100457, 2023 11.
Article in English | MEDLINE | ID: mdl-37832604

ABSTRACT

Intracellular lipolysis-the enzymatic breakdown of lipid droplet-associated triacylglycerol (TAG)-depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independently of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study, we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and lipid droplet homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use noncanonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.


Subject(s)
Lipolysis , Humans , Lipase/genetics , Lipase/metabolism , Neurons/metabolism , Paraplegia , Phospholipases/metabolism , Triglycerides/metabolism
19.
Bioorg Chem ; 141: 106858, 2023 12.
Article in English | MEDLINE | ID: mdl-37774432

ABSTRACT

A series of new uncharged conjugates of adenine, 3,6-dimetyl-, 1,6-dimethyl- and 6-methyluracil with 1,2,4-triazole-3-hydroxamic and 1,2,3-triazole-4-hydroxamic acid moieties were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. It is shown that triazole-hydroxamic acids can reactivate acetylcholinesterase (AChE) inhibited by paraoxon (POX) in vitro, offering reactivation constants comparable to those of pralidoxime (2-PAM). However, in contrast to 2-PAM, triazole-hydroxamic acids demonstrated the ability to reactivate AChE in the brain of rats poisoned with POX. At a dose of 200 mg/kg (i.v.), the lead compound 3e reactivated 22.6 ± 7.3% of brain AChE in rats poisoned with POX. In a rat model of POX-induced delayed neurodegeneration, compound 3e reduced the neuronal injury labeled with FJB upon double administration 1 and 3 h after poisoning. Compound 3e was also shown to prevent memory impairment of POX-poisoned rats as tested in a Morris water maze.


Subject(s)
Cholinesterase Reactivators , Organophosphate Poisoning , Rats , Animals , Acetylcholinesterase , Cholinesterase Reactivators/pharmacology , Cholinesterase Inhibitors/pharmacology , Organophosphate Poisoning/drug therapy , Hydroxamic Acids , Paraoxon/pharmacology , Oximes/pharmacology
20.
Toxins (Basel) ; 15(9)2023 Sep 12.
Article in English | MEDLINE | ID: mdl-37755994

ABSTRACT

Bacterial organisms have undergone homologous recombination (HR) and horizontal gene transfer (HGT) multiple times during their history. These processes could increase fitness to new environments, cause specialization, the emergence of new species, and changes in virulence. Therefore, comprehensive knowledge of the impact and intensity of genetic exchanges and the location of recombination hotspots on the genome is necessary for understanding the dynamics of adaptation to various conditions. To this end, we aimed to characterize the functional impact and genomic context of computationally detected recombination events by analyzing genomic studies of any bacterial species, for which events have been detected in the last 30 years. Genomic loci where the transfer of DNA was detected pertained to mobile genetic elements (MGEs) housing genes that code for proteins engaged in distinct cellular processes, such as secretion systems, toxins, infection effectors, biosynthesis enzymes, etc. We found that all inferences fall into three main lifestyle categories, namely, ecological diversification, pathogenesis, and symbiosis. The latter primarily exhibits ancestral events, thus, possibly indicating that adaptation appears to be governed by similar recombination-dependent mechanisms.

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