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1.
Alzheimers Res Ther ; 16(1): 196, 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39232823

RESUMEN

BACKGROUND: While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. METHODS: We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer's Disease (AD) Assessment Scale's (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. RESULTS: Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94-5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19-0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05-1.39) and 0.63 units (95% CI 0.19-1.08) more severe NPS. NPS number (MMSE mean difference - 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26-2.56) and severity (MMSE - 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57-1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect - 0.08, 95% CI -0.22 to -0.002). DISCUSSION: This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.


Asunto(s)
Angiopatía Amiloide Cerebral , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Humanos , Femenino , Masculino , Anciano , Estudios Transversales , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/psicología , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Anciano de 80 o más Años
2.
Healthcare (Basel) ; 12(17)2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39273723

RESUMEN

With the growing availability of medical data and the enhanced performance of computers, new opportunities for data analysis in research are emerging. One of these modern approaches is machine learning (ML), an advanced form of statistics broadly defined as the application of complex algorithms. ML provides innovative methods for detecting patterns in complex datasets. This enables the identification of correlations or the prediction of specific events. These capabilities are especially valuable for multifactorial phenomena, such as those found in mental health and forensic psychiatry. ML also allows for the quantification of the quality of the emerging statistical model. The present study aims to examine various sociodemographic variables in order to detect differences in a sample of 370 offender patients and 370 non-offender patients, all with schizophrenia spectrum disorders, through discriminative model building using ML. In total, 48 variables were tested. Out of seven algorithms, gradient boosting emerged as the most suitable for the dataset. The discriminative model finally included three variables (regarding country of birth, residence status, and educational status) and yielded an area under the curve (AUC) of 0.65, meaning that the statistical discrimination of offender and non-offender patients based purely on the sociodemographic variables is rather poor.

4.
PLoS One ; 19(6): e0304791, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38861508

RESUMEN

The use of blockchain technology to establish food traceability chains has the potential to provide transparent information of food stuffs along the entire supply chain and also aid in the documentation or even execution of official food control processes. Particularly in instances where analytical methodologies cannot provide definitive data for food control questions under study, the certificate-based approach of a traceability chain may offer a way of regulatory control for state authorities. Given the rising importance of organic produce and the high share of eggs among the organic produce in the European Union as well as the new EU regulation on organic products and labelling that came into force in 2022, we analyze here how the control of egg production type and marketing standards can be represented within a blockchain-based traceability chain such as to maximize the traceability in compliance with the current relevant EU regulations. Intended for the use by the official food control authorities, a traceability chain for organically produced eggs in the EU would need to be implemented as a permissioned blockchain, since only select entities are allowed to participate. By combining a proof of authority consensus mechanism with issuance of soulbound tokens, we effectively suggest a 'proof of soulbound authority' consensus process. The soulbound tokens are issued throughout the administrative chain from the European Commission down to the official food control authorities in individual member states that ultimately certify the control bodies for organic produce. Despite the general limitation of not providing unambiguous proof of the organic status of individual products, the concept discussed here offers advantages with respect to allocation of authority at EU level and therefore might have positive effects beyond the traceability chain.


Asunto(s)
Huevos , Unión Europea , Huevos/análisis , Cadena de Bloques , Abastecimiento de Alimentos/normas , Alimentos Orgánicos/normas , Alimentos Orgánicos/provisión & distribución , Alimentos Orgánicos/análisis , Etiquetado de Alimentos/legislación & jurisprudencia , Etiquetado de Alimentos/normas , Humanos
5.
Nat Commun ; 15(1): 4584, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811577

RESUMEN

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.


Asunto(s)
Proteínas de la Membrana , Proteolisis , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteolisis/efectos de los fármacos , Células HEK293 , Animales , Mutación , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitinación
6.
Comput Struct Biotechnol J ; 23: 1522-1533, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38633385

RESUMEN

The complex relationships between gastrointestinal (GI) nematodes and the host gut microbiota have been implicated in key aspects of helminth disease and infection outcomes. Nevertheless, the direct and indirect mechanisms governing these interactions are, thus far, largely unknown. In this proof-of-concept study, we demonstrate that the excretory-secretory products (ESPs) and extracellular vesicles (EVs) of key GI nematodes contain peptides that, when recombinantly expressed, exert antimicrobial activity in vitro against Bacillus subtilis. In particular, using time-lapse microfluidics microscopy, we demonstrate that exposure of B. subtilis to a recombinant saposin-domain containing peptide from the 'brown stomach worm', Teladorsagia circumcincta, and a metridin-like ShK toxin from the 'barber's pole worm', Haemonchus contortus, results in cell lysis and significantly reduced growth rates. Data from this study support the hypothesis that GI nematodes may modulate the composition of the vertebrate gut microbiota directly via the secretion of antimicrobial peptides, and pave the way for future investigations aimed at deciphering the impact of such changes on the pathophysiology of GI helminth infection and disease.

7.
Int J Parasitol Drugs Drug Resist ; 24: 100522, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38295619

RESUMEN

Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) - a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide.


Asunto(s)
Antihelmínticos , Haemonchus , Nematodos , Quinolinas , Animales , Antinematodos/farmacología , Antihelmínticos/farmacología , Relación Estructura-Actividad , Caenorhabditis elegans , Quinolinas/farmacología
8.
Nat Commun ; 15(1): 275, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177131

RESUMEN

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.


Asunto(s)
Proteínas Portadoras , Quimera Dirigida a la Proteólisis , Ubiquitina-Proteína Ligasas , Proteínas Portadoras/metabolismo , Proteolisis , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
9.
ChemSusChem ; 17(3): e202300995, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-37820026

RESUMEN

The increasing need for electrochemical energy storage drives the development of post-lithium battery systems. Among the most promising new battery types are sodium-based battery systems. However, like its lithium predecessor, sodium batteries suffer from various issues like parasitic side reactions, which lead to a loss of active sodium inventory, thus reducing the capacity over time. Some problems in sodium batteries arise from an unstable solid electrolyte interphase (SEI) reducing its protective power e. g., due to increased solubility of SEI components in sodium battery systems. While it is known that the electrolyte affects the SEI structure, the exact formation mechanism of the SEI is not yet fully understood. In this study, we follow the initial SEI formation on a piece of sodium metal submerged in propylene carbonate with and without the electrolyte salt sodium perchlorate. We combine X-ray photoelectron spectroscopy, gas chromatography, and density functional theory to unravel the sudden emergence of propylene oxide after adding sodium perchlorate to the electrolyte solvent. We identify the formation of a sodium chloride layer as a crucial step in forming propylene oxide by enabling precursors formed from propylene carbonate on the sodium metal surface to undergo a ring-closing reaction. Based on our combined theoretical and experimental approach, we identify changes in the electrolyte decomposition process, propose a reaction mechanism to form propylene oxide and discuss alternatives based on known synthesis routes.

10.
Adv Sci (Weinh) ; 11(6): e2306771, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38059817

RESUMEN

Knowledge about capacity losses related to the solid electrolyte interphase (SEI) in sodium-ion batteries (SIBs) is still limited. One major challenge in SIBs is that the solubility of SEI species in liquid electrolytes is comparatively higher than the corresponding species formed in Li-ion batteries. This study sheds new light on the associated capacity losses due to initial SEI formation, SEI dissolution and subsequent SEI reformation, charge leakage via SEI and subsequent SEI growth, and diffusion-controlled sodium trapping in electrode particles. By using a variety of electrochemical cycling protocols, synchrotron-based X-ray photoelectron spectroscopy (XPS), gas chromatography coupled with mass spectrometry (GC-MS), and proton nuclear magnetic resonance (1 H-NMR) spectroscopy, capacity losses due to changes in the SEI layer during different open circuit pause times are investigated in nine different electrolyte solutions. It is shown that the amount of capacity lost depends on the interplay between the electrolyte chemistry and the thickness and stability of the SEI layer. The highest capacity loss is measured in NaPF6 in ethylene carboante mixed with diethylene carbonate electrolyte (i.e., 5 µAh h-1/2 pause or 2.78 mAh g·h-1/2 pause ) while the lowest value is found in NaTFSI in ethylene carbonate mixed with dimethoxyethance electrolyte (i.e., 1.3 µAh h-1/2 pause or 0.72 mAh g·h-1/2 pause ).

11.
Biochim Biophys Acta Biomembr ; 1866(2): 184257, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37992949

RESUMEN

Integrin α1ß1 is an adhesion receptor that binds to collagen and laminin. It regulates cell adhesion, cytoskeletal organization, and migration. The cytoplasmic tail of the α1 subunit consists of 15 amino acids and contains six positively charged lysine residues. In this study, we present evidence that the α1 integrin cytoplasmic tail (α1CT) directly associates with phosphoinositides, preferentially with phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). Since the association was disrupted by calcium, magnesium and phosphate ions, this interaction appears to be in ionic nature. Here, the peptide-lipid interaction was driven by the conserved KIGFFKR motif. The exchange of both two potential phospholipid-binding lysines for glycines in the KIGFFKR motif increased α1ß1 integrin-specific adhesion and F-actin cytoskeleton formation compared to cells expressing the unmodified α1 subunit, whereas only mutation of the second lysine at position 1171 increased levels of constitutively active α1ß1 integrins on the cell surface. In addition, enhanced focal adhesion formation and increased phosphorylation of focal adhesion kinase, but decreased phosphorylation of AKT was observed in these cells. We conclude that the KIGFFKR motif, and in particular lysine1171 is involved in the dynamic regulation of α1ß1 integrin activity and that the interaction of α1CT with phosphoinositides may contribute to this process.


Asunto(s)
Integrina alfa1 , Proteínas Proto-Oncogénicas c-akt , Integrina alfa1/química , Fosfatidilinositoles , Lisina , Adhesión Celular/genética
12.
Bioorg Med Chem ; 98: 117540, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38134663

RESUMEN

Global challenges with treatment failures and/or widespread resistance in parasitic worms against commercially available anthelmintics lend impetus to the development of new anthelmintics with novel mechanism(s) of action. The free-living nematode Caenorhabditis elegans is an important model organism used for drug discovery, including the screening and structure-activity investigation of new compounds, and target deconvolution. Previously, we conducted a whole-organism phenotypic screen of the 'Pandemic Response Box' (from Medicines for Malaria Venture, MMV) and identified a hit compound, called ABX464, with activity against C. elegans and a related, parasitic nematode, Haemonchus contortus. Here, we tested a series of 44 synthesized analogues to explore the pharmacophore of activity on C. elegans and revealed five compounds whose potency was similar or greater than that of ABX464, but which were not toxic to human hepatoma (HepG2) cells. Subsequently, we employed thermal proteome profiling (TPP), protein structure prediction and an in silico-docking algorithm to predict ABX464-target candidates. Taken together, the findings from this study contribute significantly to the early-stage drug discovery of a new nematocide based on ABX464. Future work is aimed at validating the ABX464-protein interactions identified here, and at assessing ABX464 and associated analogues against a panel of parasitic nematodes, towards developing a new anthelmintic with a mechanism of action that is distinct from any of the compounds currently-available commercially.


Asunto(s)
Antihelmínticos , Nematodos , Quinolinas , Animales , Humanos , Caenorhabditis elegans , Antihelmínticos/farmacología , Antihelmínticos/química , Relación Estructura-Actividad
13.
Nat Commun ; 14(1): 7478, 2023 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-37978176

RESUMEN

Nucleoid associated proteins (NAPs) maintain the architecture of bacterial chromosomes and regulate gene expression. Thus, their role as transcription factors may involve three-dimensional chromosome re-organisation. While this model is supported by in vitro studies, direct in vivo evidence is lacking. Here, we use RT-qPCR and 3C-qPCR to study the transcriptional and architectural profiles of the H-NS (histone-like nucleoid structuring protein)-regulated, osmoresponsive proVWX operon of Escherichia coli at different osmolarities and provide in vivo evidence for transcription regulation by NAP-mediated chromosome re-modelling in bacteria. By consolidating our in vivo investigations with earlier in vitro and in silico studies that provide mechanistic details of how H-NS re-models DNA in response to osmolarity, we report that activation of proVWX in response to a hyperosmotic shock involves the destabilization of H-NS-mediated bridges anchored between the proVWX downstream and upstream regulatory elements (DRE and URE), and between the DRE and ygaY that lies immediately downstream of proVWX. The re-establishment of these bridges upon adaptation to hyperosmolarity represses the operon. Our results also reveal additional structural features associated with changes in proVWX transcript levels such as the decompaction of local chromatin upstream of the operon, highlighting that further complexity underlies the regulation of this model operon. H-NS and H-NS-like proteins are wide-spread amongst bacteria, suggesting that chromosome re-modelling may be a typical feature of transcriptional control in bacteria.


Asunto(s)
Proteínas de Escherichia coli , Escherichia coli , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Cromatina/metabolismo , Regulación Bacteriana de la Expresión Génica , Transcripción Genética , Operón/genética
14.
Front Psychiatry ; 14: 1231851, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37711423

RESUMEN

Background: Suffering from schizophrenia spectrum disorder (SSD) has been well-established as a risk factor for offending. However, the majority of patients with an SSD do not show aggressive or criminal behavior. Yet, there is little research on clinical key features distinguishing offender from non-offender patients. Previous results point to poorer impulse control, higher levels of excitement, tension, and hostility, and worse overall cognitive functioning in offender populations. This study aimed to detect the most indicative distinguishing clinical features between forensic and general psychiatric patients with SSD based on the course of illness and the referenced hospitalization in order to facilitate a better understanding of the relationship between violent and non-violent offenses and SSD. Methods: Our study population consisted of forensic psychiatric patients (FPPs) with a diagnosis of F2x (ICD-10) or 295.x (ICD-9) and a control group of general psychiatric patients (GPPs) with the same diagnosis, totaling 740 patients. Patients were evaluated regarding their medical (and, if applicable, criminal) history and the referenced psychiatric hospitalization. Supervised machine learning (ML) was used to exploratively evaluate predictor variables and their interplay and rank them in accordance with their discriminative power. Results: Out of 194 possible predictor variables, the following 6 turned out to have the highest influence on the model: olanzapine equivalent at discharge from the referenced hospitalization, a history of antipsychotic prescription, a history of antidepressant, benzodiazepine or mood stabilizer prescription, medication compliance, outpatient treatment(s) in the past, and the necessity of compulsory measures. Out of the seven algorithms applied, gradient boosting emerged as the most suitable, with an AUC of 0.86 and a balanced accuracy of 77.5%. Discussion: Our study aimed to identify the most influential illness-related predictors, distinguishing between FPP and GPP with SSD, thus shedding light on key differences between the two groups. To our knowledge, this is the first study to compare a homogenous sample of FPP and GPP with SSD regarding their symptom severity and course of illness using highly sophisticated statistical approaches with the possibility of evaluating the interplay of all factors at play.

15.
Adv Sci (Weinh) ; 10(24): e2301874, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37348083

RESUMEN

This study addresses the improved cycling stability of Li-ion batteries based on Fe-Ti-doped LiNi0.5 Mn1.5 O4 (LNMO) high-voltage cathode active material and graphite anodes. By using 1 wt% Li3 PO4 as cathode additive, over 90% capacity retention for 1000 charge-discharge cycles and remaining capacities of 109 mAh g-1 are reached in a cell with an areal capacity of 2.3 mAh cm- 2 (potential range: 3.5-4.9 V). Cells without the additive, in contrast, suffer from accelerated capacity loss and increase polarization, resulting in capacity retention of only 78% over 1000 cycles. An electrolyte consisting of ethylene carbonate, dimethyl carbonate, and LiPF6 is used without additional additives. The significantly improved cycling stability of the full cells is mainly due to two factors, namely, the low MnIII content of the Fe-Ti-doped LNMO active material and the use of the cathode-additive Li3 PO4 . Crystalline Li3 PO4 yields a drastic reduction of transition metal deposition on the graphite anode and prevents Li loss and the propagation of cell polarization. Li3 PO4 is added to the cathode slurry that makes it a very simple and scalable process, first reported herein. The positive effects of crystalline Li3 PO4 as electrode additive, however, should apply to other cell chemistries as well.

16.
J Invest Dermatol ; 143(2): 273-283.e12, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36116506

RESUMEN

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in a substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify a high prevalence of IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine (CEL), a methylglyoxal-induced advanced glycation end-product, in the sera of patients with HS. Titers of anti-CEL IgG and IgA antibodies were highly elevated in HS compared with those in healthy controls and individuals with other inflammatory skin diseases. Strikingly, the majority of anti-CEL IgG was of the IgG2 subclass and correlated independently with both disease severity and duration. Both CEL and anti-CEL‒producing plasmablasts could be isolated directly from HS skin lesions, further confirming the disease relevance of this autoimmune response. Our data point to an aberration of the methylglyoxal pathway in HS and support an autoimmune axis in the pathogenesis of this debilitating disease.


Asunto(s)
Hidradenitis Supurativa , Humanos , Autoanticuerpos , Lisina , Calidad de Vida , Piruvaldehído , Inmunoglobulina G
17.
Opt Express ; 30(21): 38856-38879, 2022 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-36258441

RESUMEN

Multi-photon lithography allows us to complement planar photonic integrated circuits (PIC) by in-situ 3D-printed freeform waveguide structures. However, design and optimization of such freeform waveguides using time-domain Maxwell's equations solvers often requires comparatively large computational volumes, within which the structure of interest only occupies a small fraction, thus leading to poor computational efficiency. In this paper, we present a solver-independent transformation-optics-(TO-) based technique that allows to greatly reduce the computational effort related to modeling of 3D freeform waveguides. The concept relies on transforming freeform waveguides with curved trajectories into equivalent waveguide structures with modified material properties but geometrically straight trajectories, that can be efficiently fit into rather small cuboid-shaped computational volumes. We demonstrate the viability of the technique and benchmark its performance using a series of different freeform waveguides, achieving a reduction of the simulation time by a factor of 3-6 with a significant potential for further improvement. We also fabricate and experimentally test the simulated waveguides by 3D-printing on a silicon photonic chip, and we find good agreement between the simulated and the measured transmission at λ = 1550 nm.

18.
Front Pharmacol ; 13: 1014804, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36313370

RESUMEN

Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber's pole worm, and in other socioeconomically important parasitic nematodes. The "hit-to-target" workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets.

19.
Int J Parasitol ; 52(9): 581-590, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35853501

RESUMEN

The ubiquitin-mediated pathway has been comprehensively explored in the free-living nematode Caenorhabditis elegans, but very little is known about this pathway in parasitic nematodes. Here, we inferred the ubiquitination pathway for an economically significant and pathogenic nematode - Haemonchus contortus - using abundant resources available for C. elegans. We identified 215 genes encoding ubiquitin (Ub; n = 3 genes), ubiquitin-activating enzyme (E1; one), -conjugating enzymes (E2s; 21), ligases (E3s; 157) and deubiquitinating enzymes (DUBs; 33). With reference to C. elegans, Ub, E1 and E2 were relatively conserved in sequence and structure, and E3s and DUBs were divergent, likely reflecting functional and biological uniqueness in H. contortus. Most genes encoding ubiquitination pathway components exhibit high transcription in the egg compared with other stages, indicating marked protein homeostasis in this early developmental stage. The ubiquitination pathway model constructed for H. contortus provides a foundation to explore the ubiquitin-proteasome system, crosstalk between autophagy and the proteasome system, and the parasite-host interactions. Selected E3 and DUB proteins which are very divergent in sequence and structure from host homologues or entirely unique to H. contortus and related parasitic nematodes may represent possible anthelmintic targets.


Asunto(s)
Antihelmínticos , Haemonchus , Nematodos , Animales , Antihelmínticos/metabolismo , Caenorhabditis elegans/genética , Enzimas Desubicuitinizantes/genética , Enzimas Desubicuitinizantes/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/metabolismo , Ubiquitinación , Ubiquitinas/metabolismo
20.
Molecules ; 27(15)2022 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-35897904

RESUMEN

In this study, we address the fundamental question of the physicochemical and electrochemical properties of phosphonium-based ionic liquids containing the counter-ions bis(trifluoromethanesulfonyl)imide ([TFSI]-) and bis(fluorosulfonyl)imide ([FSI]-). To clarify these structure-property as well as structure-activity relationships, trimethyl-based alkyl- and ether-containing phosphonium ILs were systematically synthesized, and their properties, namely density, flow characteristics, alkali metal compatibility, oxidative stability, aluminum corrosivity as well as their use in Li-ion cells were examined comprehensively. The variable moiety on the phosphonium cation exhibited a chain length of four and five, respectively. The properties were discussed as a function of the side chain, counter-ion and salt addition ([Li][TFSI] or [Li][FSI]). High stability coupled with good flow characteristics were found for the phosphonium IL [P1114][TFSI] and the mixture [P1114][TFSI] + [Li][TFSI], respectively.

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