Structural Disorder Research Articles

Collagen organization and structure in FBLN5-/- mice using label-free microscopy: implications for pelvic organ prolapse.

Pelvic organ prolapse (POP) is a gynecological disorder described by the descent of superior pelvic organs into or out of the vagina as a consequence of disrupted muscles and tissue. A thorough understanding of the etiology of POP is limited by the availability of clinically relevant samples, restricting longitudinal POP studies on soft-tissue biomechanics and structure to POP-induced models such as fibulin-5 knockout (FBLN5-/- ) mice. Despite being a principal constituent in the extracellular matrix, little is known about structural perturbations to collagen networks in the FBLN5-/- mouse cervix. We identify significantly different collagen network populations in normal and prolapsed cervical cross-sections using two label-free, nonlinear microscopy techniques. Collagen in the prolapsed mouse cervix tends to be more isotropic, and displays reduced alignment persistence via 2-D Fourier transform analysis of images acquired using second harmonic generation microscopy. Furthermore, coherent Raman hyperspectral imaging revealed elevated disorder in the secondary structure of collagen in prolapsed tissues. Our results underscore the need for in situ multimodal monitoring of collagen organization to improve POP predictive capabilities.

The effect of physical activity of varying intensity on cardiomyocyte hypertrophy and myocardial polyploidy in rats

Regular exercise improves cognitive function, reduces the risk of premature death from cardiovascular disease, stroke, diabetes and improves quality of life.Aim: To study the morphological parameters of cardiomyocytes of the left ventricle of the heart and the proliferative activity of rat cardiomyocytes during physical activity of different intensity.Methodology and Research Methods. Outbred male rats (n = 30) were taken as experimental animals and divided into three series. The first series of rats were given light physical activity – the animals swam in the bath for 15 minutes. The animals of the second series were in the bath for 30 minutes (moderate severity), the third series were in the bath until they began to lose strength and sink (in 55–59 minutes). Animals were taken out of the experiment after 10 sessions of water loading. Some rats (5 animals per series) were slaughtered 30 days after the end of the experiment. After extraction, the heart was stained with hematoxylin and eosin, the amount of DNA in the nuclei of cardiomyocytes was determined, binuclear and Ki-67 positive cells were counted, and the diameter of cardiomyocytes was measured. Statistical analysis was carried out in the program “Statistica 10.0”.Results. Histological examination revealed changes only in the myocardium of the left ventricle of rats of the third series: pronounced dystrophic changes in cardiomyocytes. There were cells with necrobiosis, focal necrosis of groups of cardiomyocytes. The highest level of cardiomyocyte polyploidy occurred in the second and third series (the ratio of diploid and tetraploid cardiomyocytes in the control corresponded to 91.6 ± 7.4%; 8.2±6.3%). In these series, there was also a change in the number of binuclear cells (in the control – 12.7 ± 1.9‰). In all series of Ki-67 positive nuclei were not detected.Conclusion. Severe physical activity leads to structural disorders of the myocardium, persistent hypertrophy of cardiomyocytes and is accompanied by a decrease in the proliferative activity of cardiomyocytes.

From asynchronous states to Griffiths phases and back: Structural heterogeneity and homeostasis in excitatory-inhibitory networks

Balanced neural networks, in which excitatory and inhibitory inputs compensate each other on average, give rise to a dynamical phase dominated by fluctuations called an asynchronous state, crucial for brain functioning. However, structural disorder, which is inherent to random networks, can hinder such an excitation-inhibition balance. Indeed, structural and synaptic heterogeneities can generate extended regions in phase space akin to critical points, called Griffiths phases, with dynamical features very different from those of asynchronous states. Here we study a simple neural-network model with tunable levels of heterogeneity able to display these two types of dynamical regimes, i.e., asynchronous states and Griffiths phases, putting them together within a single phase diagram. Using this simple model, we are able to emphasize the crucial role played by synaptic plasticity and homeostasis to reestablish balance in intrinsically heterogeneous networks. Overall, we shed light onto how diverse dynamical regimes, each with different functional advantages, can emerge from a given network as a result of self-organizing homeostatic mechanisms. Published by the American Physical Society 2024

High-throughput Selection of Human de novo-emerged sORFs with High Folding Potential.

De novo genes emerge from previously noncoding stretches of the genome. Their encoded de novo proteins are generally expected to be similar to random sequences and, accordingly, with no stable tertiary fold and high predicted disorder. However, structural properties of de novo proteins and whether they differ during the stages of emergence and fixation have not been studied in depth and rely heavily on predictions. Here we generated a library of short human putative de novo proteins of varying lengths and ages and sorted the candidates according to their structural compactness and disorder propensity. Using Förster resonance energy transfer combined with Fluorescence-activated cell sorting, we were able to screen the library for most compact protein structures, as well as most elongated and flexible structures. We find that compact de novo proteins are on average slightly shorter and contain lower predicted disorder than less compact ones. The predicted structures for most and least compact de novo proteins correspond to expectations in that they contain more secondary structure content or higher disorder content, respectively. Our experiments indicate that older de novo proteins have higher compactness and structural propensity compared with young ones. We discuss possible evolutionary scenarios and their implications underlying the age-dependencies of compactness and structural content of putative de novo proteins.

ICEMS Characterization of NixFe3-xO4 (0.7 ≤ x ≤ 1.7) thin films grown by ion beam sputtering on (0001) Al2O3 substrates

We report here on the ICEMS characterization of nickel ferrite (NixFe3−xO4) thin films having different nickel contents grown on alumina substrates by Ion Beam Sputtering. The spectra corresponding to the films with nominal x = 0.7, 1.0 and 1.2 are characteristic of compounds crystallizing in a spinel-related structure showing two different magnetic sextets associated with Fe3+ located in the tetrahedral and octahedral sites of such structure. The spectra show an additional broad third sextet with a large isomer shift which suggests the occurrence of electron hopping between Fe2+ and Fe3+ ions sitting in the octahedral sites. With increasing nickel content, the linewidth of the sextets increases and their corresponding hyperfine magnetic fields decrease. This is an indication of an increase in structural disorder in the deposited films as their nickel concentrations increase. The cation distribution of the iron ions over the tetrahedral and octahedral sites appears also to depend on the nickel content. The film with x = 1.2 shows a significant increase in the fraction of octahedral iron ions as compared with the expected nominal value suggesting that, for this composition, some Ni2+ could also occupy tetrahedral sites. The Mössbauer spectrum corresponding to the film with x = 1.7 shows a magnetic pattern with very broad lines similar to those shown by amorphous or disordered materials. The average isomer shift is quite high (around 0.40 mms− 1) and characteristic of Fe3+ in octahedral oxygen coordination. This indicates that for the largest nickel content studied (x = 1.7), the film does not contain Fe3+ in tetrahedral environments suggesting that the spinel structure is no longer present. This correlates well with the X-Ray Diffraction data which indicate a structural change from spinel to a disordered rock-salt structure for this particular film with high nickel content.

Decisive role of preparation technique on the structural, electrical and magnetic properties of vanadium doped ZnO nanoparticles

1% vanadium doped ZnO powders have been successfully synthesized via two different preparation techniques viz., glycine assisted combustion method and mechanical attrition method to understand their impact on the structure-property relation. X-ray Diffraction study validates the Wurtzite phase formation of ZnO with hexagonal structure. X-ray diffraction peak discloses the marked role of size and strain component. Evidently, the shift of lattice strain with the preparation techniques from compressive to tensile nature show the importance of structure property relations in the ZnO compounds. SEM micrographs depict the formation of densely populated nanograins with networking like structures which is characteristics of combustion synthesized product whereas as top down approach exhibits the presence of coarse grains amidst the broken sea of fine particles. Selected area electron diffraction (SAED) images display ring and bright circular spot pattern with changes in method of preparation, which further clarifies the distinct nature of investigated ZnO:V particles. Vibrational spectral study gives clear evidence on the structural disorder as deduced from the changes associated with longitudinal optical mode phonon scattering. Interestingly, the UV spectral study divulges the increment in optical band gap as well as a strong visible light absorption (about 30 %) for milled ZnO:V over their chemically prepared counterparts. Photoluminescence spectra of milled V doped ZnO upheld the structural disorder taken place with the suppression of Near Band Edge (NBE) transition and the shifting of broad asymmetric defect emission band towards the lower wavelength regime. Impedance study enlightens the crucial role of synthesis method with 5 times enhanced grain boundary resistance along with suppression of grain contribution in the milled samples. Magnetic study highlights the remarkable distinction of preparation route which alters the ferromagnetic ordering in the combustion synthesized samples to conventional diamagnetic signature of the host ZnO in the milled samples.

Bandgap variation in semiconductor thin films of the solid solution (CdTe)1-x(In2Te3)x deposited by RF sputtering

(CdTe)1-x(In2Te3)x films, with 0.1 ≤ x ≤ 1, were deposited by radio frequency sputtering on glass substrates employing different targets, prepared for each composition. The x-ray diffractograms were consistent with substitutional In incorporation into the CdTe lattice up to a value of x = 0.2. For higher In contents, the films presented structural disorder without reaching full amorphous characteristics. For x = 1, corresponding to In2Te3, preferential growth was observed. The bandgap of the solid solution varied between 1.46 and 1.2 eV, reaching a maximum of 1.58 eV for x = 0.3. For both end binary compounds the random incorporation of a third chemical element produced a significant broadening of the Raman modes consistent with a reduction of the lifetime of the optical phonons. The electrical resistivity was dependent on the Cd concentration reaching a minimum for x = 0.8.

CYLD alleviates NLRP3 inflammasome-mediated pyroptosis in osteoporosis by deubiquitinating WNK1

BackgroundOsteoporosis (OP) is the result of bone mass reduction and bone structure disorder. Bone marrow mesenchymal stem cells (BMSCs) are the main source of osteogenic precursor cells involved in adult bone remodeling. The involvement of the deubiquitinating enzyme CYLD in OP has recently been discovered. However, the detailed role and mechanism of CYLD remain unknown.MethodsThe OP mouse model was established by performing ovariectomy (OVX) on mice. Hematoxylin and eosin staining, Masson and Immunohistochemical staining were used to assess pathologic changes. Real-time quantitative PCR, Western blot, and immunofluorescence were employed to assess the expression levels of CYLD, WNK1, NLRP3 and osteogenesis-related molecules. The binding relationship between CYLD and WNK1 was validated through a co-immunoprecipitation assay. The osteogenic capacity of BMSCs was determined using Alkaline phosphatase (ALP) and alizarin red staining (ARS). Protein ubiquitination was evaluated by a ubiquitination assay.ResultsThe levels of both CYLD and WNK1 were decreased in bone tissues and BMSCs of OVX mice. Overexpression of CYLD or WNK1 induced osteogenic differentiation in BMSCs. Additionally, NLRP3 inflammation was activated in OVX mice, but its activation was attenuated upon overexpression of CYLD or WNK1. CYLD was observed to reduce the ubiquitination of WNK1, thereby enhancing its protein stability and leading to the inactivation of NLRP3 inflammation. However, the protective effects of CYLD on osteogenic differentiation and NLRP3 inflammation inactivation were diminished upon silencing of WNK1.ConclusionCYLD mitigates NLRP3 inflammasome-triggered pyroptosis in osteoporosis through its deubiquitination of WNK1.

The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy.

Epilepsy is a multifaceted neurological syndrome characterized by recurrent, spontaneous, and synchronous seizures. The pathogenesis of epilepsy, known as epileptogenesis, involves intricate changes in neurons, neuroglia, and endothelium, leading to structural and functional disorders within neurovascular units and culminating in the development of spontaneous epilepsy. Although current research on epilepsy treatments primarily centers around anti-seizure drugs, it is imperative to seek effective interventions capable of disrupting epileptogenesis. To this end, a comprehensive exploration of the changes and the molecular mechanisms underlying epileptogenesis holds the promise of identifying vital biomarkers for accurate diagnosis and potential therapeutic targets. Emphasizing early diagnosis and timely intervention is paramount, as it stands to significantly improve patient prognosis and alleviate the socioeconomic burden. In this review, we highlight the changes and molecular mechanisms of the neurovascular unit in epileptogenesis and provide a theoretical basis for identifying biomarkers and drug targets.

Evaluation of the Bioenergy Potential of Blends (Green Coconut Shells and Fish Scales) as a Feedstock in Thermochemical Processes for Clean Energy Production

Brazil is among the world’s largest producers of green coconut, which contributes to inappropriate disposal and socioenvironmental impacts. Concomitantly, some of its coastal cities produce a great diversity of fish and large amounts of solid waste. This paper reports on the use of samples of fish scales (100FS) and green coconut shells (100GCS) and their mixtures in 75%FS:25%GCS (B25), 50%FS:50%GCS (B50), and 25%FS:75%GCS (B75) proportions and quantification of their Higher Heating Values (HHV) and Lower Heating Values (LHV), and Ultimate (UA) and Proximate Analyses (PA). Their thermal behavior was investigated by thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC), whereas scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), and Fourier transformed infrared (FTIR) were employed for analyses of their physicochemical and morphostructural properties. When compared to in natura samples, SEM images of the blends detected a structural disorder and a highly fibrous structure with an elongated chain and surface roughness. HHV were superior in samples with 100GCS (16.64 MJ kg−1), B75 (15.80 MJ kg−1), and B50 (14.98 MJ kg−1), and lower in B25 (14.16 MJ kg−1) and 100FS (13.03 MJ kg−1), with acceptable values for different biomasses. TG/DTG and DSC curves showed similarities among the samples, with the detection of their main thermoconversion stages. According to the data, the samples can be applied as renewable energy sources to mitigate socioecological illnesses and social vulnerabilities resulting from the archaic and inadequate management of solid waste.

Charged Exciton Generation by Curvature-Induced Band Gap Fluctuations in Structurally Disordered Two-Dimensional Semiconductors.

Curvature is a general factor for various two-dimensional (2D) materials due to their flexibility, which is not yet fully unveiled to control their physical properties. In particular, the effect of structural disorder with random curvature formation on excitons in 2D semiconductors is not fully understood. Here, the correlation between structural disorder and exciton formation in monolayer MoS2 on SiO2 was investigated by using photoluminescence (PL) and Raman spectroscopy. We found that the curvature-induced charge localization along with band gap fluctuations aid the formation of the localized charged excitons (such as trions). In the substrate-supported region, the trion population is enhanced by a localized charge due to the microscopic random bending strain, while the trion is suppressed in the suspended region which exhibits negligible bending strain, anomalously even though the dielectric screening effect is lower than that of the supported region. The redistribution of each exciton by the bending strain leads to a huge variation (∼100-fold) in PL intensity between the supported and suspended regions, which cannot be fully comprehended by external potential disorders such as a random distribution of charged impurities. The peak position of PL in MoS2/SiO2 is inversely proportional to the Raman peak position of E12g, indicating that the bending strain is correlated with PL. The supported regions exhibit an indirect portion that was not shown in the suspended regions or atomically flat substrates. The understanding of the structural disorder effect on excitons provides a fundamental path for optoelectronics and strain engineering of 2D semiconductors.

Effect of vitamin D in experimental varicocele model in rats

Purpose: Varicocele is a pathological condition that affects approximately 20% of adult men, causing infertility and sperm deterioration. The aim of our study was to investigate the efficacy of vitamin D (Vit. D) in the pathophysiology of varicocele. We performed biochemical, gene expression analyses and histopathological to evaluate the efficacy of vitamin D in the experimental varicocele model.
 Materials and Methods: In the study, 30 adult male Wistar Albino rats were used. The rats were divided into 3 groups equally as control group, experimental group (varicocele), treatment group (varicocele + D vit.). The treatment group received 500 IU/kg D vit. intramuscularly.
 Results: Histopathological, TRPM2-8 gene expression and biochemical analyses were performed on testicular and blood samples collected at the end of the experiment. The experimental group showed a deterioration in tubular structure, a decrease in total antioxidant levels and an increase in total oxidant levels. The treatment group, on the other hand, showed an increase in TAS, a decrease in TOS and a beneficial improvement in tubular structure disorders. Analysis of gene expression levels showed that TRPM2-8 expression levels were significantly increased in the varicocele group and decreased in the treatment group.
 Conclusion: In the varicocele model, the use of vitamin D had a significant effect on TRPM2-8 gene level, pathological seminiferous tubules and biochemical values. Further studies are needed to determine the clinical application of vitamin D in varicocele disease.

The Roles of the Golgi in Various Diseases

The primary function of the Golgi is to perform post-translational modifications on proteins, allow them to be transported within the cell. The Golgi has more functions in the cell, according to research into its unknown structure and functions. It has been discovered that, in addition to substance process and transport, it plays a role in autophagy, lipid formation, calcium homeostasis, and apoptosis regulation.
 The fact that the Golgi has so many tasks has caused question marks about what kind of illnesses or diseases it can cause in case of a problem with Golgi. A mutation at Golgi can disrupt its function by cause of the Golgi fragmentation. It can be seized by living organisms or molecules, called infectious agents, outside the mutation. Disintegration and disorders in the Golgi structure and function are examples of neurodegenerative diseases and cancer. In addition, studies prove that the SARS-CoV-2 virus, which causes pandemic in the world, is also linked to the Golgi. The diseases that can be caused by the Golgi are highlighted in this review, as are treatment studies. Treatment strategies for the Golgi that causes many diseases are still developing and studies are ongoing.The primary function of the Golgi apparatus is to perform post-translational modifications on proteins, allowing them to be transported within the cell. The Golgi has more functions in the cell, according to research into its unknown structure and functions. It has been discovered that, in addition to substance processing and transport, it plays a role in autophagy, lipid formation, calcium homeostasis, and apoptosis regulation. The fact that Golgi has so many tasks has caused question marks about what kind of illnesses or diseases it can cause in case of a problem with Golgi. A mutation at Golgi can disrupt its function by causing Golgi fragmentation. It can be seized by living organisms or molecules, called infectious agents, outside the mutation. Disintegration and disorders in Golgi structure and function are examples of neurodegenerative diseases and cancer. In addition, studies prove that the SARS-CoV-2 virus, which causes pandemics in the world, is also linked to Golgi. The diseases that can be caused by Golgi are highlighted in this review, as are treatment studies. Treatment strategies for Golgi device that causes many diseases are still developing and studies are ongoing.

Prenatal, Perinatal And Postnatal Risk Factors From Mother And Child To The Incidence Of Epilepsy

BACKGROUND: Epilepsy is a health problem that affects sufferers and their families, characterized by at least two seizures without provocation with an interval of more than 24 hours between seizures, one seizure without provocation with the possibility of recurring within 10 years, a diagnosis of epilepsy syndrome has been established. The risk of epilepsy can be influenced by the condition of the mother and child in the prenatal, perinatal and postnatal periods. AIMS: This study analyzed the risks of several prenatal, perinatal, and postnatal factors of mother and child as risk factors for epilepsy incidence. METHOD: A case control study was conducted at RSUP Dr. Kariadi Semarang from July 2022 to March 2023. A total of 90 eligible subjects were divided into 45 case with epilepsy and 45 control with a non-epileptic diagnosis. Inclusion criteria were aged over 17 years to 40 years and exclusion criteria were subjects with mothers who had died or could not be interviewed, data were incomplete and had structural brain disorders or other diseases with clinical symptoms of seizures for the control group. The data obtained were analyzed using chi squares test for bivariate association, followed by multivariate analysis with multiple logistic regression. RESULT: Maternal age during pregnancy (p=0.016), low birth weight (p=0.007), surgical birth (p=0.004), head trauma at the age of less than 6 years (p=0.008) have been shown to influence the occurrence of epilepsy with significance respectively. CONCLUSION: Prenatal factors of the mother which is maternal age during pregnancy, perinatal and postnatal factors of the child which are low birth weight, surgical birth, and head trauma at the age of less than 6 years are risk factors that influence the occurrence of adulthood epilepsy.

The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.

Owing to the widespread use and improper emissions of carbon black nanoparticles (CBNPs), the adverse effects of CBNPs on human health have attracted much attention. In toxicological research, carbon black is frequently utilized as a negative control because of its low toxicity and poor solubility. However, recent studies have indicated that inhalation exposure to CBNPs could be a risk factor for severe and prolonged pulmonary inflammation and fibrosis. At present, the pathogenesis of pulmonary fibrosis induced by CBNPs is still not fully elucidated, but it is known that with small particle size and large surface area, CBNPs are more easily ingested by cells, leading to organelle damage and abnormal interactions between organelles. Damaged organelle and abnormal organelles interactions lead to cell structure and function disorders, which is one of the important factors in the development and occurrence of various diseases, including pulmonary fibrosis. This review offers a comprehensive analysis of organelle structure, function, and interaction mechanisms, while also summarizing the research advancements in organelles and organelle interactions in CBNPs-induced pulmonary fibrosis.

Recurrent Hemoptysis Post Re-Embolization in a 49 Year-Old Male with Post Tuberculosis Lung Disease (PTLD) and Bronchiectasis

Introduction: Hemoptysis is a symptom of lung disease, could be caused by lung infections, structural disorders of the lung, malignancy or disorders from outside of the lung. One of the pulmonary intervention for hemoptysis is embolization with a success rate > 70%, but the recurrence rate reaches 10-55%. The prognosis is poor depending on the amount of bleeding (untreated cases can have a mortality risk of over 50%), etiology and presence of recurrences.
 Case Illustration: A 49-year-old Male came to the policlinic with recurrent hemoptysis for a year. Non-smoker. History of Lung Tuberculosis (TB), completed treatment 15 years ago. Imaging result showed widening of the right subcostal artery, right posterior intercostal artery, bronchiectasis, active lung tuberculosis and left pulmonary emphysema. First embolization was done during Anti-Tuberculosis Drug (ATD) treatment for 6 months. Symptom of hemoptysis reappeared, then second embolization and fiber optic bronchoscopy (FOB) was performed. From the evaluation, he was diagnosed with infected bronchiectasis and PTLD, therefore given antibiotic medications for 2 weeks.
 Discussion: Embolization had been done twice in this case, no significant result. Based on literature, recurrent hemoptysis can still occur with a percentage about 10-55% after embolization and in this case, it might be caused by previous lung structural disorder and lung infections (Lung TB and Infected bronchiectasis).
 Conclusion: Although embolization has a success rate of > 70% for hemoptysis treatment, recurrence can still occur and highly dependent on the cause itself and patient's previous lung condition.
 Keywords: Hemoptysis, Embolization, Bronchiectasis, FOB, Lung TB, PTLD, ATD

Sacubitril/Valsartan Alleviates Cardiac Remodeling and Dysfunction in L-NAME-Induced Hypertension and Hypertensive Heart Disease.

There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease.

Dynamic three-dimensional structures of a metal–organic framework captured with femtosecond serial crystallography

Crystalline systems consisting of small-molecule building blocks have emerged as promising materials with diverse applications. It is of great importance to characterize not only their static structures but also the conversion of their structures in response to external stimuli. Femtosecond time-resolved crystallography has the potential to probe the real-time dynamics of structural transitions, but, thus far, this has not been realized for chemical reactions in non-biological crystals. In this study, we applied time-resolved serial femtosecond crystallography (TR-SFX), a powerful technique for visualizing protein structural dynamics, to a metal–organic framework, consisting of Fe porphyrins and hexazirconium nodes, and elucidated its structural dynamics. The time-resolved electron density maps derived from the TR-SFX data unveil trifurcating structural pathways: coherent oscillatory movements of Zr and Fe atoms, a transient structure with the Fe porphyrins and Zr6 nodes undergoing doming and disordering movements, respectively, and a vibrationally hot structure with isotropic structural disorder. These findings demonstrate the feasibility of using TR-SFX to study chemical systems.

Investigation the mechanism of iron overload-induced colonic inflammation following ferric citrate exposure

Iron overload occurs due to excessive iron intake compared to the body’s demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.

Abstract 3545: Atlas of therapeutic targets: Evolution of druggable proteome

Abstract Selection of therapeutic targets and modalities is of fundamental importance in drug discovery, as it can have a direct impact on the economics of drug discovery as well as its success rate. With the advancement of chem-bio and proteomics methods together with advent of artificial intelligence, the scope of the druggable proteome is expanding. The choice of drug targets gains further importance as we link it to potential clinical efficacy and safety, genetic variation and patient populations. Drug targets are often selected based on inadequate understanding of target biology, tractability by existing toolbox of therapeutic modalities and insufficient insight into possible clinical outcome. We have developed an “Atlas of Therapeutic Targets”, an interactive resource that provides classification of drug target families with linked information on clinical and investigational drugs. The atlas also provides key insights and score for tractability of targets with various therapeutic modalities. Particularly, our scoring system grades the targets on dimensions such as ligandability, involvement in protein-protein complexes, structural disorder, hotspot analysis and cross-referencing with known targets, thus yielding a total tractability score of 1-10. Dissection of targets based on such dimensions, enables critical evaluation therapeutic modalities as well tools and methodologies needed for their conversion into successful drug discovery programs. We curate 900+ human drug targets, analysis of which indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms. This atlas will be available as a resource for the wide drug discovery community. Citation Format: Ivan Babic, Elmar Nurmemmedov. Atlas of therapeutic targets: Evolution of druggable proteome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3545.