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We present the visualization of the experimental valence electron-density distribution (EDD) in the isolated 1,2-digermacyclobutadiene ring system, revealing the unique 4π electron-delocalization on the four-membered Ge2C2 ring. A remarkably high Möbius 4π-electron aromatic character in the Ge2C2 ring can be suggested from theoretical calculations, in sharp contrast to the significant antiaromaticity of the all-carbon cyclobutadiene ring.

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A variety of 10 polysaccharide motifs comprising naturally inspired sequences of monosaccharide building blocks are studied to understand the inter-relation between their structural and mechanical behaviors. Equilibrium and steered molecular dynamics (SMD) simulations are employed to investigate the stress-strain relationships and the associated conformational flips of the pyranose moieties along the polysaccharide chains. The presence of a variety of glycosidic linkages connecting the diverse monosaccharide units along with chain-branching in some cases induce wide diversity in the carbohydrate-Ramachandran plots of the glycosidic dihedrals. Similar variations are observed in the Cremer-Pople ring puckering patterns across the polysaccharide variants. The work further provides a comparison between the experimentally obtained atomic force microscopic data of mechanical stretching for some polysaccharides with the stress-strain curves generated from our SMD simulations. Out of all the systems studied, pectin having an axial-axial orientation of the glycosidic linkage showed maximum stretching potential, while acetan-M, with an equatorial-equatorial disposition of the glycosidic bond, stretched the least. The experimental Young's modulus of the corresponding natural polysaccharides could be reasonably compared to the values obtained from our simulation models. Force distribution analysis is done to understand the propagation of punctual stress in the polysaccharides under SMD conditions. Changes in local electrophilicity or nucleophilicity of atomic centers in puckered pyranose rings are estimated through the condensed Fukui functions. All of this information can help understand the physical behavior and chemical reactivity of complex polysaccharides in a complicated milieu of electronic and steric effects experienced by them.

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Skin aging is a complex phenomenon influenced by multiple internal and external factors that can lead to significant changes in skin structure, particularly the degradation of key extracellular matrix (ECM) components such as collagen and elastic fibers in the dermis. In this study, we aimed to meticulously assess the morphological changes within these critical fibrous ECM elements in the dermis of the same volunteer at age 47 and 10 years later (2012 to 2022). Using advanced histological staining techniques, we examined the distribution and characteristics of ECM components, including type I collagen, type III collagen, and elastic fibers. Morphological analysis, facilitated by hematoxylin and eosin staining, allowed for an accurate assessment of fiber bundle thickness and a quantification of collagen and elastic fiber areas. In addition, we used the generalized Pareto distribution for histogram modeling to refine our statistical analyses. This research represents a pioneering effort to examine changes in ECM fiber material, specifically within the male dermis over a decade-long period. Our findings reveal substantial changes in the organization of type I collagen within the ECM, providing insight into the dynamic processes underlying skin aging.

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Emodin is an important anthraquinone compound with good anti-inflammatory activity in Chinese traditional medicine rhubarb. Detailed spatial distribution information in bio-tissues plays an important role in revealing the pharmacodynamics, toxicology and chemical mechanism of emodin. Herein, the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-TOF-MSI) analytical method was established to obtain information on the spatial and temporal changes of emodin in multiple mouse tissue sections (heart, liver, spleen, lung, kidney, and brain) after intraperitoneal injection of emodin in mice. The measurements were accomplished in the negative ion mode in the range of m/z 250-285 Da with a spatial resolution on 40 µm. It was found that emodin was predominantly distributed in the arteriolar vascular region of the heart, the capsule region of the spleen, and the cortex of the kidney. Moreover, the MALDI-TOF-MSI result implied that emodin might be distributed in the brain. These more detailed spatial distribution information provides the significant reference for investigating the action mechanism of emodin, which cannot be obtained from conventional LC-MS analysis. The distribution trend of emodin in the results of MALDI-TOF-MSI analysis agreed with the ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) results well, demonstrating the complementarity and reliability of the established MALDI-TOF-MSI method. Our work provided a label-free molecular imaging method to investigate the precise spatial distribution of emodin in various organs, which prove great potential in studying the effective substances and mechanism of rhubarb.

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CONTEXT: Ubiquitin-like with PHD and RING finger domain containing protein 1 (UHRF1) is responsible for preserving the stability of genomic methylation through the recruitment of DNA methyltransferase 1 (DNMT1). However, the interaction between Developmental pluripotency associated 3 (DPPA3) and the pre-PHD-PHD (PPHD) domain of UHRF1 hinders the nuclear localization of UHRF1. This disruption has implications for potential cancer treatment strategies. Drugs that mimic the binding pattern between DPPA3 and PPHD could offer a promising approach to cancer treatment. Our study reveals that DPPA3 undergoes dissociation from the C-terminal through three different modes of helix unfolding. Furthermore, we have identified key residue pairs involved in this dissociation process and potential drug-targeting residues. These findings offer valuable insights into the dissociation mechanism of DPPA3 from PPHD and have the potential to inform the design of novel drugs targeting UHRF1 for cancer therapy. METHODS: To comprehend the dissociation process and binding patterns of PPHD-DPPA3, we employed enhanced sampling techniques, including steered molecular dynamics (SMD) and conventional molecular dynamics (cMD). Additionally, we utilized self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. The Gromacs software was used for performing molecular dynamics simulations, and the AMBER FF14SB force field was applied to the protein.

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Imaging neuronal architecture has been a recurrent challenge over the years, and the localization of synaptic proteins is a frequent challenge in neuroscience. To quantitatively detect and analyze the structure of synapses, we recently developed free SODA software to detect the association of pre and postsynaptic proteins. To fully take advantage of spatial distribution analysis in complex cells, such as neurons, we also selected some new dyes for plasma membrane labeling. Using Icy SODA plugin, we could detect and analyze synaptic association in both conventional and single molecule localization microscopy, giving access to a molecular map at the nanoscale level. To replace those molecular distributions within the neuronal three-dimensional (3D) shape, we used MemBright probes and 3D STORM analysis to decipher the entire 3D shape of various dendritic spine types at the single-molecule resolution level. We report here the example of synaptic proteins within neuronal mask, but these tools have a broader spectrum of interest since they can be used whatever the proteins or the cellular type. Altogether with SODA plugin, MemBright probes thus provide the perfect toolkit to decipher a nanometric molecular map of proteins within a 3D cellular context.

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BACKGROUND: Analysis of tongue movement would benefit from a reference showcasing healthy tongue capability. We aimed to develop a reference of tongue capability and evaluated the role of visual feedback on the expression of movement. METHODS: Using a wireless tracking intraoral wearable device, we composed probability distributions of the tongue tip as subjects were asked to explore the entire sensing surface area. Half of the 32 subjects received live visual feedback of the location of the center of the tongue tip contact. RESULTS: We observed that the visual feedback group was 51.0% more consistent with each other in the position domain, explored 21.5% more sensing surface area, and was 50.7% more uniformly distributed. We found less consistent results when we evaluated velocity and acceleration. CONCLUSION: Visual feedback best established a healthy capability reference which can be used for designing new interfaces, quantifying tongue ability, developing new diagnostic and rehabilitation techniques, and studying underlying mechanisms of tongue motor control.

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Heavy metal pollution in water caused by industrial activities has become a global environmental issue. Among them, manganese mining and smelting activities have caused the combined pollution of Cr(VI) and Mn(II) in water, posing a serious ecotoxicological risk to ecological environments and human health. To efficiently remove Cr(VI) and Mn(II) from wastewater, a novel biochar supported nanoscale zerovalent iron-calcium alginate composite (CA/nZVI/RSBC) was synthesized by liquid-phase reduction and calcium alginate embedding methods. The adsorption performance and mechanisms of Cr(VI) and Mn(II) by CA/nZVI/RSBC were investigated. The maximum adsorption capacities of Cr(VI) and Mn(II) onto CA/nZVI/RSBC fitted by the Langmuir model were 5.38 and 39.78 mg/g, respectively, which were much higher than the pristine biochar. The iron release from CA/nZVI/RSBC was comparatively lower than that of nZVI/RSBC. Mn(II) presence enhanced the reduction of Cr(VI) by CA/nZVI/RSBC. The results of XRD, XPS, and site energy distribution analysis indicated that redox was the predominant mechanism of Cr(VI) adsorption, while electrostatic attraction dominated Mn(II) adsorption. This study provides a novel alternative way for the simultaneous removal of Cr(VI) and Mn(II) in wastewater.

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Microplastic (MP) pollution of agricultural soils has caused global alarm over its widespread distribution and potential risks to terrestrial ecosystems and human health. This study assessed human health based on exposure to soil MPs through a comprehensive investigation of the factors influencing their occurrence and spatial distribution on Hainan Island, South China. The results showed that the abundance of soil MPs was 1128.6 ± 391.5 items·kg-1, whereas the normalized abundance of MPs based on using a power-law function was 19,261.4 items·kg-1. Regarding the extent of population exposure to agricultural soil MPs, the average daily exposure dose (pADD) model revealed that using mass as an indicator to assess the health risks associated with MP intake is more reliable than using abundance. However, abundance-based exposure assessments are also relevant because MPs with smaller particle sizes are more harmful to human health. Moreover, for adults, the normalized pADD values based on abundance and mass were 1.68E-02 item MPs·kg BW-1·d-1 and 7.23E-02 mg MPs·kg BW-1·d-1, respectively. Although the multidimensionality of MPs should be further aligned and quantified, the preliminary findings of this study contribute to the development of human health risk assessment frameworks for soil MPs.

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The size of nanoparticles is a critical parameter with regard to their performance. Therefore, precise measurement of the size distribution is often required. While electron microscopy (EM) is a useful tool to image large numbers of particles at once, manual analysis of individual particles in EM images is a time-consuming and labor-intensive task. Therefore, reliable automatic detection methods have long been desired. This paper introduces a novel automatic particle analysis software package based on the circular Hough transform (CHT). Our software package includes novel features to enhance precise particle analysis capabilities. We applied the CHT algorithm in an iterative workflow, which ensures optimal detection over wide radius intervals, to deal with overlapping particles. In addition, smart intensity criteria were implemented to resolve common difficult cases that lead to false particle detection. Implementing these criteria enabled an effective and precise analysis by minimizing detection of false particles. Overall, our approach showed reliable particle analysis results by resolving common types of particle overlaps and deformation with only negligible errors.

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Background: Violence against doctors is a global concern. Violent injuries against doctors occur periodically in China. At least one violent injury event was witnessed by 54% of medical staff against doctors in 2020. Analyzing this phenomenon and establishing preventive measures is a common concern of the medical and criminal communities. Methods: This study comprised 712 injury events against doctors in Guangdong Province, China, from January 2019 to October 2022. The spatial distribution and spatiotemporal changes of these events were analyzed using ArcGIS and Excel software. Results: Considering the geographical distribution, the injury events against doctors showed a three-level concentric circle pattern where, Guangzhou and Shenzhen, adjacent cities, and distant cities were ranked as high, medium, and low-risk areas, respectively. In temporal distribution, the periods of high incidence were 9-11, 14-15, and 20 o'clock, and the incidence tended to be similar daily, with the peaks in June and July. Conclusion: We found that the risk level of injury events against doctors was positively correlated with the medical resources level in the areas. The injury event incidence was higher during the daytime working hours. Temperature may have a strong positive effect on injury events against doctors.

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Grinding is a critical surface-finishing process in the manufacturing industry. One of the challenging problems is that the specific grinding energy is greater than in ordinary procedures, while energy efficiency is lower. However, an integrated energy model and analysis of energy distribution during grinding is still lacking. To bridge this gap, the grinding time history is first built to describe the cyclic movement during air-cuttings, feedings, and cuttings. Steady and transient power features during high-speed rotations along the spindle and repeated intermittent feeding movements along the x-, y-, and z-axes are also analysed. Energy prediction models, which include specific movement stages such as cutting-in, stable cutting, and cutting-out along the spindle, as well as infeed and turning along the three infeed axes, are then established. To investigate model parameters, 10 experimental groups were analysed using the Gauss-Newton gradient method. Four testing trials demonstrate that the accuracy of the suggested model is acceptable, with errors of 5%. Energy efficiency and energy distributions for various components and motion stages are also analysed. Low-power chip design, lightweight worktable utilization, and minimal lubricant quantities are advised. Furthermore, it is an excellent choice for optimizing grinding parameters in current equipment.

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The fight against alien invasive insect pests of plants in the urban environment often affects varied sectors of the economy, landscape gardening, public health, and ecology. This paper focuses on the evolution of the red palm weevil in San Benedetto del Tronto, a coastal urban area in central Italy. We investigated the evolution of this insect pest of palm trees in the 2013-2020 period, considering both the effectiveness of the chemicals used and their potentially harmful effects. With a multidisciplinary approach, we carried out a spatio-temporal analysis of the extent and mode of pest spread over time using historical aerial photos, freely available remote sensing images, and field surveys integrated in a GIS environment. We also assessed the toxicity risk associated with the chemicals used to protect the palms from the red weevil. The fight against this weevil is now concentrated in specific areas such as parks, roads, villas, hotels, farmhouses, and nurseries. The preventive chemical treatments applied are very effective in preserving the palms, but they show a toxic potential for all organisms. We discuss current local management of this pest, focusing on several aspects involved in the fight against this beetle in an urban area.

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Nanoparticles have unique properties that make them useful in a variety of applications, but their potential toxicity raises concerns about their safety. Accurate characterization of nanoparticles is essential for understanding their behavior and potential risks. In this study, we employed machine learning algorithms to automatically identify nanoparticles based on their morphological parameters, achieving high classification accuracy. Our results demonstrate the effectiveness of machine learning for nanoparticle identification and highlight the need for more precise characterization methods to ensure their safe use in various applications.

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The recent surge of therapeutic interest in recombinant adeno-associated viral (AAV) vectors for targeted DNA delivery has brought analytical ultracentrifugation (AUC) into the spotlight. A major concern during formulation of AAV therapeutics is purity of the active species (DNA-containing capsid, or "filled capsids"). Insertion of DNA into AAV is not a highly efficient process; thus, a significant amount of empty and partial/intermediate AAV molecules may exist. Recent guidance from the FDA includes limiting the presence of empty AAV capsids and other impurities to reduce immunotoxicity. While chromatographic techniques (SEC, SEC-MALS, AEX) are often used for empty and full capsid quantitation due to the ease of accessibility and familiarity among most biochemists, the resolution and sensitivity attained by sedimentation velocity (SV-AUC) in the formulation buffer and purification buffers is unmatched. Approaches for using SV-AUC to determine the empty-to-full capsid ratio have already been discussed by others; however, in this report, we focus on the importance of characterizing other impurities, such as free DNA, partially filled capsids, and aggregates that are recognized as species of concern for immunotoxicity. We also demonstrate the usefulness of applying multiple analyses (e.g., c(s), g(s*), WDA) in confirming the presence of and determining the hydrodynamic parameters of these various species.

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Permeabilization of the mitochondrial outer membrane-a point of no return in apoptotic regulation-is tightly controlled by proteins of the Bcl-2 family. Apoptotic inhibitor Bcl-xL is an important member of this family, responsible for blocking the permeabilization, and is also a promising target for anti-cancer drugs. Bcl-xL exists in the following conformations, each believed to play a role in the inhibition of apoptosis: (i) a soluble folded conformation, (ii) a membrane-anchored (by its C-terminal α8 helix) form, which retains the same fold as in solution and (iii) refolded membrane-inserted conformations, for which no structural data are available. In this review, we present the summary of the application of various methods of fluorescence spectroscopy for studying membrane interaction of Bcl-xL, and specifically the formation of the refolded inserted conformation. We discuss the application of environment-sensitive probes, Förster resonance energy transfer, fluorescence correlation spectroscopy, and fluorescent quenching for structural, thermodynamic, and functional characterization of protein-lipid interactions, which can benefit studies of other members of Bcl-2 (e.g., Bax, BAK, Bid). The conformational switching between various conformations of Bcl-xL depends on the presence of divalent cations, pH and lipid composition. This insertion-refolding transition also results in the release of the BH4 regulatory domain from the folded structure of Bcl-xL, which is relevant to the lipid-regulated conversion between canonical and non-canonical modes of apoptotic inhibition.

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Allenes (>C=C=C<) are classified as cumulated dienes with a linear structure and an sp-hybridized central carbon atom. We have synthesized and isolated a stable 2-germapropadiene with bulky silyl substituents. The 2-germapropadiene allene moiety adopts a linear structure both in the solid state and in solution. An X-ray diffraction electron-density-distribution (EDD) analysis of this 2-germapropadiene confirmed the linear C=Ge=C geometry with a formally sp-hybridized germanium atom that bears two orthogonal C=Ge π-bonds. Based on detailed structural and computational studies, we concluded that the linear geometry of the isolated 2-germapropadiene most likely arises from the negative hyperconjugation of the silyl substituents at the terminal carbon atoms. The 2-germapropadiene reacts rapidly with nucleophiles, indicating that the linearly oriented germanium atom is highly electrophilic.

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BACKGROUND: DNA mismatch repair deficiency (dMMR) testing is crucial for detection of microsatellite unstable (MSI) tumors. MSI is detected by aberrant indel length distributions of microsatellite markers, either by visual inspection of PCR-fragment length profiles or by automated bioinformatic scoring on next-generation sequencing (NGS) data. The former is time-consuming and low-throughput while the latter typically relies on simplified binary scoring of a single parameter of the indel distribution. The purpose of this study was to use machine learning to process the full complexity of indel distributions and integrate it into a robust script for screening of dMMR on small gene panel-based NGS data of clinical tumor samples without paired normal tissue. METHODS: Scikit-learn was used to train 7 models on normalized read depth data of 36 microsatellite loci in a cohort of 133 MMR proficient (pMMR) and 46 dMMR tumor samples, taking loss of MLH1/MSH2/PMS2/MSH6 protein expression as reference method. After selection of the optimal model and microsatellite panel the two top-performing models per locus (logistic regression and support vector machine) were integrated into a novel script (DeltaMSI) for combined prediction of MSI status on 28 marker loci at sample level. Diagnostic performance of DeltaMSI was compared to that of mSINGS, a widely used script for MSI detection on unpaired tumor samples. The robustness of DeltaMSI was evaluated on 1072 unselected, consecutive solid tumor samples in a real-world setting sequenced using capture chemistry, and 116 solid tumor samples sequenced by amplicon chemistry. Likelihood ratios were used to select result intervals with clinical validity. RESULTS: DeltaMSI achieved higher robustness at equal diagnostic power (AUC = 0.950; 95% CI 0.910-0.975) as compared to mSINGS (AUC = 0.876; 95% CI 0.823-0.918). Its sensitivity of 90% at 100% specificity indicated its clinical potential for high-throughput MSI screening in all tumor types. Clinical Trial Number/IRB B1172020000040, Ethical Committee, AZ Delta General Hospital.

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PM2.5 is an important indicator reflecting air quality variations. Currently, environmental pollution related issues have become more severe that significantly threaten human health. The current study is an attempt to analyze the spatio-dynamic characteristics of PM2.5 in Nigeria based on the directional distribution and trend clustering analysis from 2001 to 2019. The results indicated that PM2.5 concentration increased in most of the Nigerian states, particularly in mid-northern and southern states. The lowest PM2.5 concentration in Nigeria is even beyond the interim target-1 (35 µg/m3) of the WHO. During the study period, the average PM2.5 concentration increased at a growth rate of 0.2 µg/m3/yr from 69 µg/m3 to 81 µg/m3. The growth rate varied from region to region. Kano, Jigawa, Katsina, Bauchi, Yobe, and Zamfara experienced the fastest growth rate of 0.9 µg/m3/yr with 77.9 µg/m3 mean concentration. The median center of the national average PM2.5 moved toward the north indicating the highest PM2.5 concentration in northern states. The Saharan desert dust is the dominant source of PM2.5 in northern areas. Moreover, agricultural practices and deforestation activities along with low rainfall increase desertification and air pollution in these regions. Health risks increased in most of the mid-northern and southern states. The extent of ultra-high health risk (UHR) areas corresponding to the 8×104-7.3×106 µg⋅person/m3 increased from 1.5% to 2.8%. Mainly Kano, Lagos, Oyo, Edo, Osun, Ekiti, southeastern Kwara, Kogi, Enugu, Anambra, Northeastern Imo, Abia, River, Delta, northeastern Bayelsa, Akwa Ibom, Ebonyi, Abuja, Northern Kaduna, Katsina, Jigawa, central Sokoto, northeastern Zamfara, central Borno, central Adamawa, and northwestern Plateau are under UHR areas.

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Time-resolved femtosecond-stimulated Raman spectroscopy (FSRS) provides valuable information on the structural dynamics of biomolecules. However, FSRS has been applied mainly up to the nanoseconds regime and above 700 cm-1, which covers only part of the spectrum of biologically relevant time scales and Raman shifts. Here we report on a broadband (~200-2200 cm-1) dual transient visible absorption (visTA)/FSRS set-up that can accommodate time delays from a few femtoseconds to several hundreds of microseconds after illumination with an actinic pump. The extended time scale and wavenumber range allowed us to monitor the complete excited-state dynamics of the biological chromophore flavin mononucleotide (FMN), both free in solution and embedded in two variants of the bacterial light-oxygen-voltage (LOV) photoreceptor EL222. The observed lifetimes and intermediate states (singlet, triplet, and adduct) are in agreement with previous time-resolved infrared spectroscopy experiments. Importantly, we found evidence for additional dynamical events, particularly upon analysis of the low-frequency Raman region below 1000 cm-1. We show that fs-to-sub-ms visTA/FSRS with a broad wavenumber range is a useful tool to characterize short-lived conformationally excited states in flavoproteins and potentially other light-responsive proteins.

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