Corrigendum to "Revisiting misfolding propensity of serum amyloid A1: Special focus on the signal peptide region" [Biochem. Biophys. Rep. 31 (2022) 1-9/101284].

[This corrects the article DOI: 10.1016/j.bbrep.2022.101284.].

Molecular Dynamic Simulations for Biopolymers with Biomedical Applications.

Computational modeling (CM) is a versatile scientific methodology used to examine the properties and behavior of complex systems, such as polymeric materials for biomedical bioengineering. CM has emerged as a primary tool for predicting, setting up, and interpreting experimental results. Integrating in silico and in vitro experiments accelerates scientific advancements, yielding quicker results at a reduced cost. While CM is a mature discipline, its use in biomedical engineering for biopolymer materials has only recently gained prominence. In biopolymer biomedical engineering, CM focuses on three key research areas: (A) Computer-aided design (CAD/CAM) utilizes specialized software to design and model biopolymers for various biomedical applications. This technology allows researchers to create precise three-dimensional models of biopolymers, taking into account their chemical, structural, and functional properties. These models can be used to enhance the structure of biopolymers and improve their effectiveness in specific medical applications. (B) Finite element analysis, a computational technique used to analyze and solve problems in engineering and physics. This approach divides the physical domain into small finite elements with simple geometric shapes. This computational technique enables the study and understanding of the mechanical and structural behavior of biopolymers in biomedical environments. (C) Molecular dynamics (MD) simulations involve using advanced computational techniques to study the behavior of biopolymers at the molecular and atomic levels. These simulations are fundamental for better understanding biological processes at the molecular level. Studying the wide-ranging uses of MD simulations in biopolymers involves examining the structural, functional, and evolutionary aspects of biomolecular systems over time. MD simulations solve Newton's equations of motion for all-atom systems, producing spatial trajectories for each atom. This provides valuable insights into properties such as water absorption on biopolymer surfaces and interactions with solid surfaces, which are crucial for assessing biomaterials. This review provides a comprehensive overview of the various applications of MD simulations in biopolymers. Additionally, it highlights the flexibility, robustness, and synergistic relationship between in silico and experimental techniques.

High-precision frequency-controlled optical phase shifter with acousto-optic devices.

A fundamental parameter to determine how electromagnetic waves interfere is their relative phase, and achieving a fine control over it enables a wide range of interferometric applications. Existing phase control methods rely on modifying the optical path length either by changing the path followed by the light or by altering the thickness or index of refraction of an optical element in the setup. In this Letter, we present a novel, to the best of our knowledge, method, based on acousto-optic modulators (AOMs), which allows adjusting the phase by shifting the frequency of the light in a segment of its path. Since the amount of phase shift depends on the length of the segment, an optical fiber is used to realize a 2π shift. Two experimental implementations are described which deal with different sources of phase fluctuations. The first addresses fluctuations resulting from the optical fiber, while the second tackles unwanted variations originating from the AOMs.

1,4-Diurea- and 1,4-Dithiourea-Substituted Aromatic Derivatives Selectively Inhibit α-Synuclein Oligomer Formation In Vitro.

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting the elderly population worldwide. In PD, the misfolding of α-synuclein (α-syn) results in the formation of inclusions referred to as Lewy bodies (LB) in midbrain neurons of the substantia nigra and other specific brain localizations, which is associated with neurodegeneration. There are no approved strategies to reduce the formation of LB in the neurons of patients with PD. Our drug discovery program focuses on the synthesis of urea and thiourea compounds coupled with aminoindole moieties to abrogate α-syn aggregation and to slow down the progression of PD. We synthesized several urea and thiourea analogues with a central 1,4-phenyl diurea/thiourea linkage and evaluated their effectiveness in reducing α-syn aggregation with a special focus on the selective inhibition of oligomer formation among other proteins. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), as well as M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. Our results identified compound 1 as the best compound in reducing α-syn fibril formation via ThT assays. The antioligomer formation of compound 1 was subsequently superseded by compound 2. Both compounds selectively curtailed the oligomer formation of α-syn but not tau 4R isoforms (0N4R, 2N4R) or p-tau (isoform 1N4R). Compounds 1 and 2 failed to abrogate tau 0N3R fibril formation by ThT and atomic force microscopy. Compound 2 was best at reducing the formation of recombinant α-syn fibrils by TEM. In contrast to compound 2, compound 1 reduced the formation of α-syn inclusions in M17D neuroblastoma cells in a dose-dependent manner. Compound 1 may provide molecular scaffolds for the optimization of symmetric molecules for its α-syn antiaggregation activity with potential therapeutic applications and development of small molecules in PD.

[Effect of weight gain on the development of gestational diabetes]. / Efecto de la ganancia ponderal en el desarrollo de diabetes gestacional.

Background: Gestational diabetes mellitus (GDM) refers to diabetes diagnosed in the second or third trimester of pregnancy. Assessing the weight gain in each pregnant women's appointment is a common task of primary care during their visit. However, the implications of this increase in weight for the development of GDM are unknown. Objective: Evaluate if the greater than expected weight gain (HEWG) in pregnancy is a risk factor for the development of GDM. Methods: Analytical, observational, longitudinal, retrolective study, which included pregnant women between 15 and 40 years of age with complete follow-up of the preg-nancy with > 2 prenatal check-ups, somatometry and complete medical history was made. During follow-up, the GPME was determined. Odds ratio (OR) and 95% confi-dence intervals (95% CI) were calculated. Variables with significance were entered into a multiple logistic regression model (MLR), where the dependent variable was DMG. The sample size calculation was for convenience. Results: 1000 pregnant women with a median age of 28 years were included. In the MLR The pre-gestational body mass index (BMI) with overweight had an RM of 1.3 (95% CI 0.86-1.98), BMI with obesity an OR of 2.57 (95% CI 1.6-4.14), the HEWG during pregnancy had an OR 1.14 95% CI (0.71-1.81), Age> 30 years shows an RM of 2.24 (95% CI 1.55-3.25). Conclusions: HEWG during pregnancy is not an independent risk factor for the devel-opment of GDM. The main ones are age> 30 years and pre-gestational obesity.

Introducción: la diabetes mellitus gestacional (DMG) se refiere a la diabetes diagnosti-cada a partir del segundo trimestre del embarazo. Evaluar el incremento de peso de mu-jeres embarazadas es una labor habitual en la consulta del primer nivel de atención. Sin embargo, se desconocen las implicaciones que tiene este incremento ponderal para el desarrollo de DMG. Objetivo: evaluar si la ganancia ponderal mayor a la esperada (GPME) en el embarazo es factor de riesgo para el desarrollo de DMG. Métodos: estudio analítico, observacional, longitudinal, retrolectivo, que incluyó a em-barazadas de 15 a 40 años con seguimiento completo del embarazo con más de dos consultas de control prenatal, somatometría e historia clínica completa. Durante el se-guimiento se determinó la GPME. Se calculó razón de momios (RM) e intervalos de confianza del 95% (IC95%). Las variables con significancia se ingresaron a un modelo de regresión logística múltiple (RLM), en donde la variable de desenlace fue DMG. Resultados: se incluyeron a 1000 embarazadas con mediana de edad de 28 años. En la RLM el índice de masa corporal (IMC) pre-gestacional con sobrepeso tuvo una RM de 1.3 (IC95%: 0.86-1.98), IMC con obesidad una RM de 2.57 (IC95%: 1.6-4.14), la GPME durante el embarazo tuvo una RM de 1.14 (IC95%: 0.71-1.81) y la edad > 30 años una RM de 2.24 (IC95%: 1.55-3.25). Conclusiones: la GPME durante el embarazo no es un factor de riesgo independiente para el desarrollo de DMG. Los principales son la edad >30 años y la obesidad preges-tacional.

Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in the geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-ß (Aß) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half of AD cases also display the presence of aggregated α-synuclein (α-syn)-containing Lewy bodies. Conversely, Lewy bodies disorders have been reported to have concomitant Aß plaques and neurofibrillary tangles. Our drug discovery program focuses on the synthesis of multitarget-directed ligands to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to slow the progression of AD and related dementias. To this end, we synthesized 11 compounds with a triazine-linker and evaluated their effectiveness in reducing α-syn, tau isoform 2N4R, and p-tau isoform 1N4R aggregation. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), and M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. We also performed disaggregation assays with isolated Aß-plaques from human AD brains. Our results demonstrated that compound 10 was effective in reducing both oligomerization and fibril formation of α-syn and tau isoform 2N4R in a dose-dependent manner via ThT and PICUP assays. Compound 10 was also effective at reducing the formation of recombinant α-syn, tau 2N4R, and p-tau 1N4R fibrils by TEM. Compound 10 reduced the development of α-syn inclusions in M17D neuroblastoma cells and stopped the seeding of tau P301S using biosensor cells. Disaggregation experiments showed smaller Aß-plaques and less paired helical filaments with compound 10. Compound 10 may provide molecular scaffolds for further optimization and preclinical studies for neurodegenerative proteinopathies.

Characterization and Evaluation of Silver Concentrations in Hydroxyapatite Powders.

The goal of this study is to evaluate the influence of the concentration of silver on the structural and antimicrobial in vitro properties of silver-doped hydroxyapatite powders obtained using the precipitation method. Different concentrations of silver were evaluated to assess the antimicrobial properties. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, scanning electron microscopy (SEM), and dispersive energy spectroscopy (EDS) were used to characterize the powders. XRD and FTIR showed that the hydroxyapatite structure is not affected by the incorporation of silver; on the other hand, EDS showed the presence of silver in the powders. Antibacterial studies showed the efficiency of hydroxyapatite powders in inhibiting bacterial growth as silver concentration increases. According to the results, silver-doped hydroxyapatite powders are suggested for use in the prevention and treatment of infections in bone and dental tissues.

5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation.

Protein misfolding results in a plethora of known diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic small molecules with the ability to reduce protein misfolding, we evaluated a set of 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) and its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), and triazine (5) linker. In addition, we explored small modifications on a very potent antioligomer 5-nitro-1,2-benzothiazol-3-amine (5-NBA) (compounds 6-13). This study aims to define the activity of BTA and its derivatives on a variety of prone-to-aggregate proteins such as transthyretin (TTR81-127, TTR101-125), α-synuclein (α-syn), and tau isoform 2N4R (tau 2N4R) through various biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation of the previously mentioned proteins after treatment with BTA and its derivatives. Antifibrillary activity was confirmed using transmission electron microscopy (TEM). Photoreactive cross-linking assay (PICUP) was utilized to detect antioligomer activity and lead to the identification of 5-NBA (at low micromolar concentration) and compound 13 (at high concentration) as the most promising in reducing oligomerization. 5-NBA and not BTA inhibited the inclusion formation based on the cell-based assay using M17D neuroblastoma cells that express inclusion-prone αS-3K::YFP. 5-NBA abrogated the fibril, oligomer, and inclusion formation in a dose-dependent manner. 5-NBA derivatives could be the key to mitigate protein aggregation. In the future, the results made from this study will provide an initial platform to generate more potent inhibitors of α-syn and tau 2N4R oligomer and fibril formation.

Discovery of 4-aminoindole carboxamide derivatives to curtail alpha-synuclein and tau isoform 2N4R oligomer formation.

Alzheimer's disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular ß-amyloid (Aß) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using α-synuclein (α-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophysical methods, such as thioflavin T fluorescence assays, photo-induced cross-linking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming α-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on α-syn and the 2N4R isoform of tau. At a concentration of 40 µM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone αSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of α-syn and tau (2N4R isoform) for further optimization prior to pre-clinical studies.

Effects of Ultraviolet Radiation on Sediment Burial Parameters and Photo-Oxidative Response of the Intertidal Anemone Anthopleura hermaphroditica.

Anthopleura hermaphroditica is an intertidal anemone that lives semi-buried in soft sediments of estuaries and releases its brooded embryos directly to the benthos, being exposed to potentially detrimental ultraviolet radiation (UVR) levels. In this study, we investigated how experimental radiation (PAR: photosynthetically active radiation; UVA: ultraviolet A radiation; and UVB: ultraviolet B radiation) influences burrowing (time, depth and speed) in adults and juveniles when they were exposed to PAR (P, 400-700 nm), PAR + UVA (PA, 315-700 nm) and PAR + UVA + UVB (PAB, 280-700 nm) experimental treatments. The role of sediment as a physical shield was also assessed by exposing anemones to these radiation treatments with and without sediment, after which lipid peroxidation, protein carbonyls and total antioxidant capacity were quantified. Our results indicate that PAB can induce a faster burial response compared to those anemones exposed only to P. PAB increased oxidative damage, especially in juveniles where oxidative damage levels were several times higher than in adults. Sediment offers protection to adults against P, PA and PAB, as significant differences in their total antioxidant capacity were observed compared to those anemones without sediment. Conversely, the presence or absence of sediment did not influence total antioxidant capacity in juveniles, which may reflect that those anemones have sufficient antioxidant defenses to minimize photooxidative damage due to their reduced tolerance to experimental radiation. Burrowing behavior is a key survival skill for juveniles after they have been released after brooding.