Understanding the Modulatory Role of E2012 on the γ-Secretase-Substrate Interaction.

Allosteric modulation plays a critical role in enzyme functionality and requires a deep understanding of the interactions between the active and allosteric sites. γ-Secretase (GS) is a key therapeutic target in the treatment of Alzheimer's disease (AD), through its role in the synthesis of amyloid ß peptides that accumulate in AD patients. This study explores the structure and dynamic effects of GS modulation by E2012 binding, employing well-tempered metadynamics and conventional molecular dynamics simulations across three binding scenarios: (1) GS enzyme with and without L458 inhibitor, (2) the GS-substrate complex together with the modulator E2012 in two different binding modes, and (3) E2012 interacting with a C99 substrate fragment. Our findings reveal that the presence of L458 induces conformational changes that contribute to stabilization of the GS enzyme dynamics, previously reported as a key factor that allowed the resolution of the cryo-EM structure and the enhanced binding of E2012. Furthermore, we identified the most favorable binding site for E2012 within the GS-substrate complex, uncovering significant modulatory effects and a complex network of interactions that influence the position of the substrate for catalysis. In addition, we explore a potential substrate-modulator binding before the formation of the enzyme-substrate complex. The insights gained from our study emphasize the importance of these interactions in the development of potential therapeutic interventions that target the functionality of the GS enzyme in AD.

Fibrosis Management Algorithm in Secondary Liposculpture.

Liposuction is considered one of the most common procedures in plastic surgery. However, major postoperative complications such as visceral injury, fluid overload, and necrotizing fasciitis still occur. Likewise, minor complications such as ecchymosis, seromas, infections, and contour irregularities that do not threaten the life of the patient do generate significant dissatisfaction. Current evidence regarding the management of fibrosis after previous liposuction remains limited. The objective of this article is to standardize a management algorithm based on the extensive experience and successful results of the primary author. Patients who underwent secondary liposculpture between August 2022 and May 2023 were evaluated prospectively. Inclusion criteria: Women between 18 and 60 years, non-smokers, with a body mass index (BMI) <35 kg/m2, history of previous body contouring surgeries. Identification of the patient's skin condition and subcutaneous lesions in the adipose tissue were obtained in detail. Statistical analysis of preoperative and postoperative medical photographs was also performed with Fiji Biological image analyzer. Photographic analysis showed a statistically significant difference between the areas affected by fibrosis from the preoperative photos compared to that from the postoperative ones (p<.001). The most frequent clinical findings were depressions in 99% of the women (74), followed by soft nodules in 95% (70), hard nodules in 81% (61), adherences in 47% (35), and finally, cutaneous bursas in 4%. Our classification system and management algorithm for fibrosis and contour irregularities is a safe and reliable tool and results were objectively verified, yielding statistically significant outcomes.

Protein-protein association properties of human ßB2-crystallins.

Protein-protein association events are involved in many physiological and pathological processes. Cataract disease is a pathology that manifests protein aggregation of crystallins. ß-Crystallins are present in a high proportion in the eye lens. Therefore, the structural study of the dimerization properties of crystallins can shed light on the first stages of protein aggregation. In the present work, we examine the protein-protein association profiles of the human ßB2-crystallin by employing extensive coarse-grained molecular dynamics (CG-MD) and the Markov state analysis. Interestingly, our results clearly show important changes in the protein dimerization kinetics between wt-HßB2C and the deamidated systems. The two systems show dimeric conformations. However, the association and dissociation rates are very different. Our results show that the deamidated system can associate faster and dissociate slower than the wt- HßB2C. The deamidated system is in a slightly opened conformation with the Greek-key motifs well folded, suggesting that a complete unfolding of the protein is not required for aggregation. Our results describe the first stages of crystallin aggregation due to post-translational modifications.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aß, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.

A scoping review of post-diagnostic dementia supports for people with intellectual disability.

Objectives: People with intellectual disability, particularly people with Down syndrome, are at an increased risk for early-onset dementia, in comparison to people without an intellectual disability. The aim of this review was to scope the current landscape of post-diagnostic dementia supports for people with intellectual disability.Method: A systematic search of five electronic databases (CINAHL, Medline, PsycArticles, PsycInfo and Web of Science) was conducted for this scoping review. Results were screened independently by two reviewers, with a third reviewer for arbitration where necessary.Results: Forty-two studies met the inclusion criteria, and relevant information was extracted. The articles included focussed on the experiences of people with intellectual disability and dementia, as well as the role of carers, family members and staff. Key themes included ageing in place, environmental supports for people with intellectual disability and dementia, dementia-specific interventions and therapies, as well as the feasibility of these interventions. Besides the studies that focussed on these themes, other studies focussed on staff training and family supports.Conclusion: This review highlights the importance of implementing timely and appropriate post-diagnostic supports for people living with intellectual disability and dementia. More controlled trials are required on post-diagnostic dementia supports for people with intellectual disability.

A Review of Foods of Plant Origin as Sources of Vitamins with Proven Activity in Oxidative Stress Prevention according to EFSA Scientific Evidence.

Beyond their nutritional benefits, vitamins could decrease the risk of chronic diseases due to their potent antioxidant capacity. The present work is aimed at reviewing the state of the art regarding (1) the vitamins involved in oxidative stress prevention in accordance with the requirements established by the European Food Safety Authority (EFSA) and (2) the foods of plant origin that are sources of those vitamins and have potential benefits against oxidative stress in humans. According to the European regulations based on EFSA scientific evidence, riboflavin, vitamin C, and vitamin E are those vitamins subjected to the approved health claim "contribute to the protection of cells from oxidative stress". Scientific studies conducted in humans with some natural food sources of riboflavin (almonds, wheat germ, mushrooms, oat bran), vitamin C (guava, kale, black currant, Brussels sprouts, broccoli, orange), and vitamin E (hazelnuts, almonds, peanuts, pistachio nuts, extra virgin olive oil, dates, rye) have been performed and published in the literature. However, no food of plant origin has obtained a favorable EFSA opinion to substantiate the approval of health claims related to its potential properties related to oxidative stress prevention. Further studies (concretely, well-controlled human intervention studies) must be carried out in accordance with EFSA requirements to provide the highest level of scientific evidence that could demonstrate the potential relationship between foods of plant origin and antioxidant capacity. This review could be useful for the scientific community to study the application of health claims referring to the antioxidant capacity potentially exerted by foods of plant origin.

Autoimmune and autoinflammatory conditions after COVID-19 vaccination. New case reports and updated literature review.

Autoimmunity linked to COVID-19 immunization has been recorded throughout the pandemic. Herein we present six new patients who experienced relapses of previous autoimmune disease (AD) or developed a new autoimmune or autoinflammatory condition following vaccination. In addition, we documented additional cases through a systematic review of the literature up to August 1st, 2022, in which 464 studies (928 cases) were included. The majority of patients (53.6%) were women, with a median age of 48 years (IQR: 34 to 66). The median period between immunization and the start of symptoms was eight days (IQR: 3 to 14). New-onset conditions were observed in 81.5% (n: 756) of the cases. The most common diseases associated with new-onset events following vaccination were immune thrombocytopenia, myocarditis, and Guillain-Barré syndrome. In contrast, immune thrombocytopenia, psoriasis, IgA nephropathy, and systemic lupus erythematosus were the most common illnesses associated with relapsing episodes (18.5%, n: 172). The first dosage was linked with new-onset events (69.8% vs. 59.3%, P = 0.0100), whereas the second dose was related to relapsing disease (29.5% vs. 59.3%, P = 0.0159). New-onset conditions and relapsing diseases were more common in women (51.5% and 62.9%, respectively; P = 0.0081). The groups were evenly balanced in age. No deaths were recorded after the disease relapsed, while 4.7% of patients with new-onset conditions died (P = 0.0013). In conclusion, there may be an association between COVID-19 vaccination and autoimmune and inflammatory diseases. Some ADs seem to be more common than others. Vaccines and SARS-CoV-2 may induce autoimmunity through similar mechanisms. Large, well-controlled studies are warranted to validate this relationship and assess additional variables such as genetic and other environmental factors.

Molecular basis of Toxoplasma gondii oryzalin resistance from a novel α-tubulin binding site model.

Oryzalin (ORY) is a dinitroaniline derivative that inhibits the microtubule polymerization in plants and parasitic protozoa by selectively binding to the α-tubulin subunit. This herbicidal agent exhibits good antiprotozoal activity against major human parasites, such as Toxoplasma gondii (toxoplasmosis), Leishmania mexicana (leishmaniasis), and Plasmodium falciparum (malaria). Previous chemical mutagenesis assays on T. gondii α-tubulin (TgAT) have identified key mutations that lead to ORY resistance. Herein, we employed alchemical free energy methods and molecular dynamics simulations to determine if the ORY resistance mutations either decrease the TgAT's affinity of the compound or increase the protein stability. Our results here suggest that L136F and V202F mutations significantly decrease the affinity of ORY to TgAT, while T239I and V252L mutations diminish TgAT's flexibility. On the other hand, protein stability predictors determined that R243S mutation reduces TgAT stability due to the loss of its salt bridge interaction with E27. Interestingly, molecular dynamics simulations confirm that the loss of this key interaction leads to ORY binding site closure. Our study provides a better insight into the TgAT-ORY interaction, further supporting our recently proposed ORY-binding site.

Mechanistic regulation of γ-secretase by their substrates.

γ-Secretase (GS) is a transmembrane (TM) enzyme that plays important roles in the processing of approximately 90 substrates. The amyloid precursor protein (APP) is one of these substrates, and the peptides derived from their processing are related with the development of Alzheimer's disease. However, the mechanistic process involved in the GS substrate processing and regulation remains elusive. In this work, we employed extensive atomistic molecular dynamics simulations, reduction dimensionality, and network analysis to understand the dynamic behavior of GS in its apo form and bound to transmembrane fragments of APP-C99, APP-C83, and Notch. An evaluation of the global conformation of the enzyme revealed that GS and GS-C83 systems display extended and compact conformations. However, systems with long extracellular N-terminal substrates, such as APP-C99 and Notch, preferred compact conformations. Interestingly, our network analysis revealed that the NCT-lobule (residues 223-248) plays a crucial role in the communication and the dynamics between the extracellular and TM components of the enzyme, impacting the catalytic site. In our GS-C99 simulated system, the interaction paths of the substrate processing region encompass the ε-site and ζ-site, leading to more imprecise positioning of the catalytic residue Asp385. Conversely, our GS-C83 simulated system shows more stability at the ε-site. Our observations shed light on the important mechanics of the fascinating GS architecture and may contribute to propose new GS modulators able to impact on the Alzheimer's disease treatment.

Psychotropic drugs intake in people aging with intellectual disability: Prevalence and predictors.

BACKGROUND: Psychotropic medication is frequently administered to people with intellectual disability with mental health and/or behavioural problems, instead of other non-pharmacological interventions. This study describes the mental health and behavioural problems of people aging with intellectual disability, their psychotropic medication intake, and the factors contributing to a greater medication intake. METHOD: The sample consisted of 991 people with intellectual disability over 45 years. Descriptive statistics and multinominal logistic regression were carried out. RESULTS: Antipsychotics were the most used psychotropic drug. Older people with mild intellectual disability living in institutions and affected by mental health and behavioural problems were more likely to take larger amounts of psychotropic medication. CONCLUSIONS: Antipsychotics continue to be widely used by people with intellectual disability and mental and behavioural health problems, especially those in institutionalised settings. Future research should consider if medication intake could be reduced providing better supports in the community and non-pharmacological interventions.

Clinical characteristics of admission for mental illness in a Regional Psychiatric Hospitalization Unit. Descriptive study 2008-2018 / Características clínicas del ingreso por enfermedad mental en una Unidad de Hospitalización Psiquiátrica Comarcal. Estudio descriptivo 2008-2018.

Objective: To describe the admissions of patients diagnosed with severe mental illness (SMI) and anxiety disorder in a regional hospital; to explore factors related to the patient's referrer upon admission and prolonged stay. Materials and methods: Cross-sectional study of episodes of admission to the regional Psychiatric Hospitalization Unit over a period of 11 years with ICD-10 diagnostic codesF20-29, F30-39, F60-69 and F40-48. The data was extracted through the Admissions Unit and the information from the electronic medical record. For the statistical treatment, descriptive or inferential tests were used with a confidence level of 95%. Results: 961 patients were included (2,324 total discharges), aged 40.8±14.0 years. The most frequent reasons for admission were: positive symptoms (agitation, delusions and hallucinations), followed by suicidal ideation and attempt. The main remitting agent of the patients was the family itself. Approximately 1/5 of the cases were referred by the health system itself, and » of those admitted had self-excluded themselves from specialized supervision for more than a year. Conclusions: The problems that caused the admission and its origin, as well as its lack of follow-up, can be considered as a clear opportunity for improvement in the follow-up of patients with severe mental illness. An orientation towards proactivity, acting before the decompensation, would contribute to improving the care and quality of life of patients with severe mental illness and their environment.

Objetivo: Describir los ingresos de pacientes diagnosticados de enfermedad mental grave y trastorno de ansiedad en un hospital comarcal; explorar los factores relacionados con la derivación del paciente al ingreso y con estancia prolongada. Materiales y métodos: Estudio de corte transversal de los episodios de ingreso en la Unidad de Hospitalización Psiquiátrica comarcal en un periodo de 11 años con los códigos diagnósticos CIE-10 F20-29, F30-39, F60-69 y F40-48. Se extrajeron los datos a través de la Unidad de Admisión y la información de la historia clínica electrónica. Para el tratamiento estadístico se usaron pruebas descriptivas o inferenciales con nivel de confianza del 95%. Resultados: Se incluyeron 961 pacientes (2.324 altas totales), con edad de 40,8±14,0 años. Los motivos más frecuentes de ingreso fueron: síntomas positivos (agitación, delirios y alucinaciones), seguidos de ideación e intento de suicidio. El principal agente remisor de los pacientes fue la propia familia. Aproximadamente 1/5 de casos fue derivado por el propio sistema sanitario, y » de los ingresados se había autoexcluido de la supervisión especializada durante más de un año. Conclusiones: Los problemas causantes del ingreso y su procedencia, así como su falta de seguimiento, pueden considerarse como una oportunidad clara de mejora en el seguimiento del paciente con enfermedad mental grave. Una orientación hacia la proactividad, actuando antes de la descompensación, contribuiría a mejorar la asistencia y calidad de vida de los pacientes con enfermedad mental grave y su entorno.

Mitochondria and calcium defects correlate with axonal dysfunction in GDAP1-related Charcot-Marie-Tooth mouse model.

Ganglioside-induced differentiation associated protein 1 (GDAP1) gene encodes a protein of the mitochondrial outer membrane and of the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs) and lysosomes. Since mutations in GDAP1 cause Charcot-Marie-Tooth, an inherited motor and sensory neuropathy, its function is essential for peripheral nerve physiology. Our previous studies showed structural and functional defects in mitochondria and their contacts when GDAP1 is depleted. Nevertheless, the underlying axonal pathophysiological events remain unclear. Here, we have used embryonic motor neurons (eMNs) cultures from Gdap1 knockout (Gdap1-/-) mice to investigate in vivo mitochondria and calcium homeostasis in the axons. We imaged mitochondrial axonal transport and we found a defective pattern in the Gdap1-/- eMNs. We also detected pathological and functional mitochondria membrane abnormalities with a drop in ATP production and a deteriorated bioenergetic status. Another consequence of the loss of GDAP1 in the soma and axons of eMNs was the in vivo increase calcium levels in both basal conditions and during recovery after neuronal stimulation with glutamate. Further, we found that glutamate-stimulation of respiration was lower in Gdap1-/- eMNs showing that the basal bioenergetics failure jeopardizes a full respiratory response and prevents a rapid return of calcium to basal levels. Together, our results demonstrate that the loss of GDAP1 critically compromises the morphology and function of mitochondria and its relationship with calcium homeostasis in the soma and axons, offering important insight into the cellular mechanisms associated with axonal degeneration of GDAP1-related CMT neuropathies and the relevance that axon length may have.

Electron Donor-Acceptor Properties of Different Muscarinic Ligands: On the Road to Control Schizophrenia.

Schizophrenia is a severe neuropsychiatric disorder that deteriorates perception, affection, and cognitive mental functions. The current treatments are mainly focused on the dopamine system, but the so-named dopamine hypothesis of schizophrenia fails to explain all the symptoms. Previous studies have shown that there is a reciprocal relationship between muscarinic acetylcholine receptors and dopamine receptor function. Some muscarinic ligands show antidopaminergic activity, and therefore, they should have some antipsychotic efficacy. In this work, conceptual density functional theory is employed to analyze the properties of acetylcholine's agonists, partial agonists, or antagonists. The aim is to establish a classification of the antipsychotic-like or pro-psychotic activities of these molecules based on the electron-donor and electron-acceptor properties. Most of the agonists and antagonists are better electron donors and worse electron acceptors than partial agonists. We found that acetylcholine antagonists that clinically promote psychotic symptoms are good electron-donor molecules, and acetylcholine agonists that clinically relieve symptoms of psychosis are good electron donors. These results represent a further advance on the road to understanding the charge-transfer properties of drugs used as possible treatments for schizophrenia.

The Contribution of the Ankyrin Repeat Domain of TRPV1 as a Thermal Module.

The TRPV1 cation nonselective ion channel plays an essential role in thermosensation and perception of other noxious stimuli. TRPV1 can be activated by low extracellular pH, high temperature, or naturally occurring pungent molecules such as allicin, capsaicin, or resiniferatoxin. Its noxious thermal sensitivity makes it an important participant as a thermal sensor in mammals. However, details of the mechanism of channel activation by increases in temperature remain unclear. Here, we used a combination of approaches to try to understand the role of the ankyrin repeat domain (ARD) in channel behavior. First, a computational modeling approach by coarse-grained molecular dynamics simulation of the whole TRPV1 embedded in a phosphatidylcholine and phosphatidylethanolamine membrane provides insight into the dynamics of this channel domain. Global analysis of the structural ensemble shows that the ARD is a region that sustains high fluctuations during dynamics at different temperatures. We then performed biochemical and thermal stability studies of the purified ARD by the means of circular dichroism and tryptophan fluorescence and demonstrate that this region undergoes structural changes at similar temperatures that lead to TRPV1 activation. Our data suggest that the ARD is a dynamic module and that it may participate in controlling the temperature sensitivity of TRPV1.

Recruitment strategies: non-donor segmentation based on intrinsic and extrinsic stimuli.

BACKGROUND AND OBJECTIVES: Non-donor behaviour can be influenced by many variables, both intrinsic and extrinsic, which differ among individuals. The aim of this study was therefore to segment Spanish non-donors based on criteria such as barriers and motivations, which influence the decision to donate for the first time, with the aim of improving the efficiency and effectiveness of recruitment actions. MATERIALS AND METHODS: A total of 2383 non-donors residing in Spain evaluated 21 barriers and 25 motivations through an online self-administered survey distributed by blood transfusion centres, which are responsible for donations in Spain, and several Spanish universities. After validating these scales and determining the underlying categories in each of them, latent class/profile analysis was performed to segment non-donors. RESULTS: Spanish non-donors were divided into six clusters. According to their barriers and motivations, the following labels were assigned: (1) 'Impure altruists', (2) 'I want to, but make it easy for me', (3) 'Free-riders', (4) 'Reciprocal altruists', (5) 'I can't because I'm scared' and (6) 'I want to, but I can't'. Specific marketing actions were proposed for each cluster based on their characteristics, prioritizing them depending on their attractiveness. CONCLUSION: The scales which were designed to evaluate barriers and motivations make a solid contribution to the existing literature due to their holistic, integrative nature. The existence of differentiated clusters and the lack of resources of blood transfusion centres make it clear that there is a need to define and implement targeted marketing strategies.

Effects of Mutating Trp42 Residue on γD-Crystallin Stability.

Oligomerization and aggregation of γD-crystallins (HγDC) in the eye lens is one of the main causes of cataract development. To date, several congenital mutations related to this protein are known to promote the formation of aggregates. Previous studies have demonstrated that mutations in W42 residue of HγDC lead to the generation of partially unfolded intermediates that are more prone to aggregate. To understand the role of W42 in the stability of HγDC, we performed alchemical free-energy calculations and all-atom molecular dynamics simulations of different W42 mutant models. Our results suggest that substitution of W42 by small size and/or polar residues promotes HγDC denaturation due to the entry of water molecules into the hydrophobic core of the N-terminal domain. Similar behavior was observed in the C-terminal domain of HγDC when mutating the W130 residue located in a homologous position. Moreover, the exposure of the hydrophobic core residues could lead to the formation of aggregation-prone partially unfolded species. Overall, this study takes a step toward understanding the role of HγDC in cataract development.

Conformational analysis by NMR and molecular dynamics of adamantane-doxorubicin prodrugs and their assemblies with ß-cyclodextrin: A focus on the design of platforms for controlled drug delivery.

Nanoscale design and construction of affinity-based drug delivery systems (ADDS) is an active research area with enormous potential for the improvement of cancer treatment. For the therapeutic load of these ADDS, a promising strategy is the design of pH-sensitive prodrugs based on the construction of conjugates between adamantane and doxorubicin (Ad-Dox), which stands out as an excellent model system to obtain novel supramolecular materials. Construction of these prodrugs involves a modification of three zones of doxorubicin which in principle does not affect the action mechanism: the carbonyl group C13 (hydrazone linker), the primary alcohol neighboring the carbonyl (ester linker) and the 3' amino group of daunosamine sugar (amide linker). These modifications are aimed to improve the efficacy and reduce the systemic toxicity of the drug chemotherapy by controlling its release in cancer cells. In this work, we performed 2D NMR experiments and molecular dynamics simulations to characterize the conformational changes of three constructed prodrugs. Our results demonstrated that ring A and the daunsamine sugar of the hydrazone and amide linkers conserve the half-chair state 9H8, while the ester linker disrupts this conformation. Our study also showed that the hydrazone-linked compound (Ad-h-Dox) does not modify the conformation of the original drug and maintains cytotoxic activity. Moreover, the inclusion complex (IC) of Ad-h-Dox with ß-cyclodextrin (ßCD) generated a highly soluble platform in water, whereas the ester-linked compound (Ad-e-Dox) causes the loss of biological activity. This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system.

Exploring the folding process of human ßB2-crystallin using multiscale molecular dynamics and the Markov state model.

Adequate knowledge of protein conformations is crucial for understanding their function and their association properties with other proteins. The cataract disease is correlated with conformational changes in key proteins called crystallins. These changes are due to mutations or post-translational modifications that may lead to protein unfolding, and thus the formation of aggregate states. Human ßB2-crystallin (HßB2C) is found in high proportion in the eye lens, and its mutations are related to some cataracts. HßB2C also associates into dimers, tetramers, and other higher-order supramolecular complexes. However, it is the only protein of the ßγ-crystallin family that has been found in an extended conformation. Therefore, we hypothesize that the extended conformation is not energetically favourable and that HßB2C may adopt a closed (completely folded) conformation, similar to the other members of the ßγ-crystallin family. To corroborate this hypothesis, we performed extensive molecular dynamics simulations of HßB2C in its monomeric and dimeric conformations, using all-atom and coarse-grained scales. We employed Markov state model (MSM) analysis to characterize the conformational and kinetically relevant states in the folding process of monomeric HßB2C. The MSM analysis clearly shows that HßB2C adopts a completely folded structure, and this conformation is the most kinetically and energetically favourable one. In contrast, the extended conformations are kinetically unstable and energetically unfavourable. Our MSM analysis also reveals a key metastable state, which is particularly interesting because it is from this state that the folded state is reached. The folded state is stabilized by the formation of two salt bridges between the residue-pairs E74-R187 and R97-E166 and the two hydrophobic residue-pairs V59-L164 and V72-V151. Furthermore, free energy surface (FES) analysis revealed that the HßB2C dimer with both monomers in a closed conformation (face-en-face dimer) is energetically more stable than the domain-swapped dimer (crystallographic structure). The results presented in this report shed light on the molecular details of the folding mechanism of HßB2C in an aqueous environment and may contribute to interpreting different experimental findings. Finally, a detailed knowledge of HßB2C folding may be key to the rational design of potential molecules to treat cataract disease.

Nanocrystals of Novel Valerolactam-Fenbendazole Hybrid with Improved in vitro Dissolution Performance.

Valero-fenbendazole (VAL-FBZ) is a novel hybrid compound with in vitro anthelmintic activity, designed and synthesized to address the global problem of resistance to anthelmintic compounds. This new molecule derives from fenbendazole (FBZ), a well-known commercially available benzimidazole used in veterinary medicine despite its poor water solubility. In this work, we report for the first time a strategy to solve the solubility problems of FBZ and VAL-FBZ by means of self-dispersible nanocrystals (SDNC). Nanocrystals were prepared by media milling followed by a spray-drying step, and a comprehensive and exhaustive structural and physicochemical characterization was carried out, in order to understand the systems and their behavior. The formulation poloxamer 188 (P188):FBZ 1:1 turned out with the best process yield (53%) and re-dispersability properties, particle size average of 258 nm, and polydispersity index of 0.2 after redispersion in water. The dissolution profile showed a markedly increased dissolution rate compared with the simple mixture of the components (80% FBZ dissolved in 15 min from the SDNC vs 14% from the control formulation). FTIR spectroscopy, thermal analysis, and X-Ray Powder Diffraction (XRPD) studies showed no chemical interactions between components and an extensive confocal Raman microscopy analysis of the formulations showed very homogeneous spatial distribution of components in the SDNC samples. This manufacturing process was then successfully transferred for preparing and characterizing VAL-FBZ:P188 (1:1) SDNC with similar results, suggesting the promising interest of a novel anthelmintic with improved biopharmaceutical behavior. In conclusion, new FBZ and VAL-FBZ SDNC with improved dissolution rate were successfully prepared and characterized. Graphical abstract.

Atomistic simulations of bulk heterojunctions to evaluate the structural and packing properties of new predicted donors in OPVs.

Organic photovoltaic materials (OPVs), with low cost and structure flexibility, are of great interest and importance for their application in solar cell device development. However, the optimization of new OPV structures and the study of the structure arrangements and packing morphologies when materials are blended takes time and consumes raw materials, thus theoretical models could be of considerable value. In this work, we performed molecular dynamics simulations of present OPVs to understand the morphological packing of the donor-acceptor (DA) phases and DA heterojunction during evaporation and annealing processes, following inter and intramolecular properties like frontier orbitals, π-π stacking, coordination, distances, angles, and aggregation. Our considered donor molecules were selected from already proved experimental studies and also from predicted optimal compounds, designed through high throughput studies. The acceptor molecule employed in all our studied systems was PCBM ([6,6]-phenyl-C61-butyric acid methyl ester). Furthermore, we also analyze the influence of including different lateral aliphatic chains on the structural properties of the resulting DA packing morphologies. Our results can guide the design of new OPVs and subsequent studies applying charge transport and charge separation models.