Photothrombotic stroke (PTS) stimulates the level of N- and C-terminal fragments of Amyloid precursor protein (APP) growth in the cytoplasm of ischemic penumbra cells not earlier but at 24 hours. Here we have shown that APP fragments are visualized in thin unmyelinated fibers of neurons, in containing mitochondria large fibers and in synapses but absent in the nuclei. At 24 hours after PTS, some elements of the destroyed tissue accumulated a significant amount of APP protein. The level of ADAM10 α-secretase decreased on the first day after PTS in the rat brain cortex and ADAM-10 co-localized with the lipid raft marker caveolin-1. PTS caused no changes in the level of β-secretase BACE1 either on the first day after PTS or in the early recovery period. The expression of proteins of the γ-secretase complex: presenilin-1 and nicastrin increased in astrocytes, but not in penumbra neurons after PTS. The β-secretase inhibitor LY2886721 did not affect the infarct size of the mouse cerebral cortex and the level of apoptosis of cells in the perifocal region after PTS. Whereas the inhibitor of γ-secretase DAPT reduced the expression of glial fibrillary acidic protein (GFAP) in astrocytes, prevented the growth of apoptosis of mouse cerebral cortex cells reducing the infarct volume on the 7th and 14th days after PTS. DAPT may be considered as a drug for stroke therapy.

Background: Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show membrane-binding capacity to red blood cells (RBCs) and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Aβ-treated RBCs. Methods: In RBCs following different treatments, ATP, 2,3 DPG, cAMP levels, and caspase 3 activity were determined by spectrophotometric and immunoassay. Results: S1P rescued the inhibition of ATP release from RBCs triggered by Aβ through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. Conclusions: These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.

Medicinal plants possess a surplus of novel and biologically active secondary metabolites that are responsible for counteracting diseases. Traditionally, Gomphandra tetrandra (Wall.) Sleumer is used to treat mental disorders. The present research was designed to explore phytochemicals from the ethanol leaf extract of Gomphandra tetrandra (Wall.) Sleumer to identify the potential pharmacophore(s) in the treatment of neurological disorders. The chemical compounds of the experimental plant were identified through GC-MS analysis. Besides, in-vitro antioxidant activity was assessed using different methods. Furthermore, in-vivo neurological activity was assessed in Swiss-albino mice. Computer aided analysis was appraised to determine the best-fit phytoconstituent of a total of fifteen identified compounds in the experimental plant extract against beta-amyloid precursor protein. The experimental extract revealed fifteen compounds in GC-MS analysis and the highest content was 9, 12, 15-octadecatrienoic acid (Z, Z, Z). Also, the extract showed potent anti-oxidant activity in in-vitro assays. Furthermore, in in-vivo neurological assays, the extract disclosed significant (p<0.05) neurological activity. The most favorable phytochemicals as neurological agents were selected via ADMET profiling and molecular docking was studied with beta-amyloid precursor protein. Moreover, in the computer aided study, 1, 5-Diphenyl-2H-1, 2, 4-triazoline-3-thione (Pub Chem CID: 2802516) was more active than other identified compounds with strong binding affinity to beta-amyloid precursor protein. The present in vivo and in silico studies revealed neuropharmacological features of G. tetrandra leaves extract as a natural agent against neurological disorders, especially Alzheimer’s disease.

Genetic discoveries related to Alzheimer’s disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. The present study aims at scanning 70 single-point mutations on the APP gene in a publicly available genetic dataset including 2.504 healthy individuals from 26 populations, and analyzing their distribution. Moreover, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations have been detected in the worldwide dataset, with several of them being specific for a single individual, population or macroarea. Patterns of segment sharing reflect recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups, and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementias.

The expanding use of devices emitting Pulsed Telecommunication Signals (PTS) has launched a serious debate over the possible effects of electromagnetic radiation (EMR) on living organisms. Our previous work has indicated that PTS exposure alters Amyloid Precursor Protein (APP) and alpha-synuclein (α-syn) metabolism in human cells of neural origin, providing a possible connection between exposure and neurodegeneration. This investigation aimed to reveal, in vitro in human non-neural cells (HEK293), the aftermath of the same exposure on the processing of APP and α-syn. Data presented here, indicate changes in APP metabolism, acquisition of different cellular topologies of the newly generated APP fragments, changes in monomeric α-syn accumulation and multimerization, indicating that APP and α-syn processing is possibly altered in the periphery by EMR. These effects are accompanied by a substantial increase in the levels of Reactive Oxygen Species (ROS). Further investigation is required in order to provide insights into the interaction of PTS with non-neural cells affecting the peripheral systemic functional stability. This is necessary because nowadays whole body human exposure from various EMR sources is a fact in normal life with the valid estimation that they may be increased in view of the forthcoming 5G telecommunications network implementation.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer’s and Huntington’s disease. Alzheimer’s disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer’s, Huntington’s, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling proteotoxicity in Alzheimer’s and Huntington’s disease-related, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO) delays age-associated paralysis in both models. This effect on paralysis was independent of protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event liking HAAO knockdown to delayed paralysis. This work demonstrates potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

Understanding the phenomena underlying the non-selective susceptibility to ischemia of py-ramidal neurons in the CA3 area of the hippocampus is important from the point of view of elu-cidating the mechanisms of memory loss and the development of post-ischemic dementia. We used an ischemic model of Alzheimer's disease to study changes in amyloid protein precursor gene expression, its cleavage enzymes and tau protein in the CA3 area of the hippocampus af-ter a 10-minute brain ischemia with 12, 18, and 24-month survival. Quantitative reverse tran-scriptase PCR assay showed that the expression of all the genes that contribute to amyloid pro-duction was dysregulated within 2 years in the CA3 area of the hippocampus after ischemia. The expression of the amyloid protein precursor gene was above the control values at all times of the study. The expression of the α-secretase gene also exceeded the control values throughout the study. In contrast, the expression of the β-secretase gene reaching its maximum increase 12 months after ischemia, was below control values after 18 months and again above control values after 24 months of survival. Presenilin 1 and 2 gene expression was significantly elevated throughout the follow-up period, with peak expression of both genes occurring 12 months after ischemia. This suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid protein precursor. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months after is-chemia. Data indicate that an episode of brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a manner dependent on modified tau protein. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area after ischemia. In addition tau protein gene modification after brain is-chemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.

Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer's disease is one of these proteinopathies. It is characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates; e.g. fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane dimerization, and subsequently Aβ aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept can be transposed to the study of other proteinopathies, providing a framework for improving our understanding of these mechanisms that devastate neuronal functions.

Data independent acquisition - mass spectrometry (DIA-MS) is becoming widely utilised for robust and accurate quantification of samples in quantitative proteomics. Here, we describe the systematic evaluation of the effects of DIA precursor mass range on total protein identification and quantification. We show that a narrow mass range of precursors (~250 m/z) for DIA-MS enables a higher number of protein identifications. Subsequent application of DIA with narrow precursor range (from 400 to 650 m/z) on Arabidopsis sample with spike-in of known proteins identified 34.7% more proteins than in conventional DIA (cDIA) with a wide precursor range of 400-1200 m/z. When combining several DIA-MS analyses with narrow precursor ranges (i.e., 400-650, 650-900 and 900-1200 m/z), we were able to quantify 10,099 protein groups with a median coefficient of variation of <6%. These findings represent a 59.4% increase in the number of proteins quantified than with cDIA analysis. This is particularly important for low abundance proteins, as exemplified by the 6-protein mix spike-in. In cDIA only 5 out of the 6-protein mix were quantified while our approach allowed accurate quantitation of all six proteins.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Pathological deposits of neurotoxin proteins within the brain, such as amyloid-Beta and hyperphosphorylated tau tangles, are prominent features in AD. The prion protein (PrP) is involved in neurodegeneration via its conversion from the normal cellular form PrPc, to the infection form PrP Sc. Some studies indicated that posttranslationally modified PrPc isoforms plays a fundamental role in AD pathological progression. Several studies have shown that interaction of Aβ oligomers with N-terminal residues of the PrPc protein region appears critical for neuronal toxicity. The PrPc-Aβ binding always occur in AD brains and is never detected in nondemented controls and the binding of Aβ aggregates to PrPc is restricted to the N-terminus of PrPc.

Ischemic heart disease is the leading cause of mortality worldwide. There is evidence of the participation of Aβ in thrombosis and clinical manifestations of acute coronary syndromes. In this study, we investigated the correlation of Aβ peptides with myocardial injury and inflammation biomarkers in acute coronary syndrome. This is a single-center, cross-sectional, observational, and correlation study that included 65 patients within the first 12 hours after symptom onset (chest pain, shoulder pain, or chest discomfort) with ST-elevation and non-ST elevation myocardial infarction who were admitted in the Coronary Care Unit, biochemical parameters of Aβ peptides levels were evaluated. Our results show that NSTEMI patients had a higher prevalence of hypertension, diabetes, smoking, and prior myocardial infarction when compared to STEMI patients. We observed a higher level of Aβ-42 in NSTEMI, but no difference in Aβ-40 levels. We also found a correlation between age and NT-proBNP with both Aβ peptides (Aβ-40, Aβ-42) in both groups. In this analysis, NSTEMI patients had higher prevalence of cardiovascular risk factors. Considering the toxic properties of Aβ-42 in coronary endothelial cells and cardiomyocytes, this peptide may be useful in risk stratification scores in patients with NSTEMI.

Aptamers are versatile oligonucleotide ligands used for molecular recognition of diverse targets. However, application of aptamers to the field of amyloid β-protein (Aβ) has been limited so far. Aβ is an intrinsically disordered protein that exists in a dynamic conformational equilibrium, presenting time-dependent ensembles of short-lived, metastable structures and assemblies that have been generally difficult to isolate and characterize. Moreover, despite understanding of potential physiological roles of Aβ, this peptide has been linked to the pathogenesis of Alzheimer disease, and its pathogenic roles remain controversial. Accumulated scientific evidence thus far highlights undesirable or nonspecific interactions between selected aptamers and different Aβ assemblies likely due to metastable nature of Aβ or inherent affinity of RNA oligonucleotides to β-sheet-rich fibrillar structures of amyloidogenic proteins. Accordingly, lessons drawn from Aβ–aptamer studies emphasize that purity and uniformity of the protein target and rigorous characterization of aptamers’ specificity are important for realizing and garnering the full potential of aptamers selected for recongizing Aβ or other intrinsically disordered proteins. This review summarizes studies of aptamers selected for recognizing different Aβ assemblies and highlights controversies, difficulties, and limitations of such studies.

In recent years there has been an increasing interest in developing novel materials based on natural biopolymers as a renewable alternative of petroleum-based plastics. The availability of proteins derived from agricultural by-products, along with their favourable properties, has fostered a renewed interest in protein-based materials, promoting research in innovative technologies. In this study we propose the use of rapeseed protein-rich meal as main ingredient for the preparation of novel sustainable materials combining excellent environmental properties such as biodegradability and renewable origin. Application as sustainable products in the present high-tech society needs modification of basic native properties of these natural compounds. The original route proposed in this paper consists in the preparation via compression moulding of flexible biomaterials stabilized by crosslinkers/chain extenders. Investigation of the effects of different denaturing and disulfide bond reducing agents, crosslinkers, and preparation conditions on the material mechanical behaviour demonstrated that the novel materials have appreciable strength and stiffness. The results show the potential of utilizing full meal from vegetable by-products to prepare protein-based materials with granted ecofriendly characteristics and mechanical properties adequate to specific structural applications.

The present article analyzes the results of recent clinical trials of beta secretase inhibition in sporadic Alzheimer’ disease (SAD), considers the striking dichotomy between successes in tests of BACE1 inhibitors in healthy subjects and familial AD (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of APP-independent, beta secretase inhibition-resistant production of beta amyloid in SAD, previously proposed by us. In the light of this concept, FAD and SAD should be regarded as distinctly different diseases as far as beta-amyloid generation mechanisms are concerned, and whereas beta secretase inhibition would be neither applicable nor effective in treatment of SAD, the BACE1 inhibitor(s) deemed failed in SAD trials could be perfectly suitable for treatment of FAD. Moreover, targeting the aspects of AD other than cleavages of the APP by beta and alpha secretases should have analogous impacts in both FAD and SAD.

Abstract: Due to their rapid evolution and their impact on health care, be-ta-lactamases, protein degrading beta-lactam antibiotics, are used as generic model of protein evolution. Therefore, we investigated the mutation effects in two distant beta-lactamases TEM-1 and CTX-M-15. Interestingly we found a site with a complex pattern of genetic interactions. Mutation G251W in TEM-1 is in-activating the protein’s function just as the reciprocal mutation W251G in CTXM-15. Phylogenetic analysis revealed that mutation G has been entrenched in TEM-1 background: while rarely observed throughout the phylogeny it is es-sential in TEM-1. Using a rescue experiment in TEM-1 G251W mutant, we could identify sites that alleviates the deviation from G to W. While few of these muta-tions could potentially involve local interactions, most of them were found on distant residues in the 3D structure. Many well-known mutations having an impact on protein stability, such as M182T, were recovered. Our results there-fore suggest that entrenchment of an amino acid may rely on diffuse interactions among multiple sites with a major impact on protein stability.

Rett syndrome (RTT) is an X-linked neurodevelopment disorder associated with the single monogenic mutation in methyl-CpG binding protein 2 (MeCP2) in up to 95% of cases. The growing number of genome-wide association studies and incomplete concordance for autoimmune diseases in monozygotic twins concur to support the involvement of environmental factors, like infectious agents or chemicals, in the breakdown of tolerance leading to autoimmunity. In fact, the coexistence of a perturbation of the immune system in RTT patients has been previously hypothesized. We herein explored the hypothesis that an autoimmune component derived from environmental bacterial infection of non typeable Haemophilus influenzae may coexist in RTT. At this purpose we screened sera from RTT syndrome patients, non-RTT pervasive developmental disorders patients and healthy controls with the hyperglucosylated adhesin protein HMW1ct(Glc) used as a precise antigen in ELISA in order to identify specific antibodies to N-glucosylation sites. Results showed that HMW1ct(Glc) is able to significantly discriminate antibodies among RTT sera and controls. Competitive ELISA confirmed the specific interaction between antibodies characteristic of RTT syndrome and the N-glucosylation motifs of the bacterial adhesin protein HMW1ct(Glc).

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography–tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that CAs in these organs primarily consist of common proteins (β2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked β2-microglobulin and lysozyme, and exhibited evident destruction of surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

L-gulonolactone oxidase enzyme (GULO) catalyzes the last step of L-ascorbic acid (vitamin C) biosynthesis. This enzymatic activity is lost in primates. The full-length rat GULO has been previously produced in plants and demonstrated to be active. In this study, we compare activity of two variants of GULO produced in Escheriachia coli cells, full-length rat GULO (fGULO) and its C-terminal catalytic domain (cGULO). The expression and purification of the recombinant proteins were optimised and their biological activity was confirmed by two methods, the GULO activity assay in the protein extracts and the ‘in-gel’ staining for GULO activity. Both variants of recombinant GULO were biologically active in both assays. However, cGULO is more promising than fGULO for ascorbic acid production because it is more efficiently produced by bacteria.

Introduction: This study aims to elucidate the clinical diagnostic value of S100 Calcium Binding Protein beta (S100B) in epilepsy, a topic of ongoing debate among European and Asian epilepsy research centres.Methods and analysis: A structured long-term research plan was developed, comprising three phases. Phase one involves observational studies investigating the correlation between S100B levels in serum or cerebrospinal fluid and epilepsy. Phase two integrates observational and randomised controlled data to establish baseline S100B levels across diverse epilepsy demographics, underpinning the predictive value of S100B for epilepsy. Phase three focuses on randomised controlled trials to evaluate the diagnostic accuracy of S100B as an epilepsy biomarker.Ethics and dissemination: All enrolled patients will provide written consent. The ethics committee of the Second People’s Hospital of Gansu Province, Affiliated Hospital of Northwest Minzu University, China, approved the study (GSSEY2022-KY009-01).Registration: The study is registered with PROSPERO (CRD42023425431).

In this manuscript, we reassess the data on beta-amyloid-induced changes of intracellular ions concentrations published previously by Abramov et al. (2003, 2004). Their observations made using high-resolution confocal microscopy with fast temporal resolution of images formed by fluorescent ion-sensitive fluorescent probes in living cells represent an unequivocal support for the amyloid channel theory. However, closer look reveals multiple facts which cannot be explained by channel formation in plasma membrane. Recently proposed amyloid degradation toxicity hypothesis provides the interpretation to these facts by considering that channels are formed in the lysosomal membranes.

Weak interaction processes continue to be hot topics in fundamental physics research. In this paper, we briefly review some recent advances in the theoretical study of beta and double-beta decays that include both the nuclear and atomic part of these processes. On the nuclear side, we present a statistical approach for the computation of the nuclear matrix elements (NME) for neutrinoless double-beta (0νββ). A range of NME values, the most probable value for NME, and the associated theoretical uncertainty are given. Correlations with other related observables are shown as well. On the atomic side, we first briefly review the methods used to get the electrons’ wave functions. Further, we use them for the computation of some relevant kinematic quantities such as Fermi functions, electron spectra and angular correlation between the emitted electrons. Then, we present applications of these calculations to the experimental data analysis related to the search of the Lorentz invariance violation in two-neutrino double-beta (2νββ) decay and description of the decay rates and decay rate ratios for allowed and unique forbidden electron capture (EC) processes.

Objective: The aim of our study was to perform a retrospective analysis of the volume of cervical screening tests, the number of patients treated with an excision method, and the incidence of invasive and non-invasive cervical during a pandemic and pre-pandemic period of 24 months. Results: There was a statistically significant age difference between the two study periods, both by the average age of patients and by age group. The mean difference was 32 years before the pan-demic and 35 years during the pandemic (p-value >0.05). The majority of patients presenting for investigations before and during the pandemic were in the 30-39-year-old age group (31.95%, respectively; 34.2% (p-value = 0.003). The biggest patient loss ratio identified by age group was in the 50–59 years: 14,53% in the pre-pandemic period and 9,1% in the pandemic period. In the pan-demic period, patients from rural areas presented in the clinical trial with a lower rate of 39.52% (83 patients) vs. 60.47% (127 patients) in urban areas. A higher percentage of patients experiencing cervicorrhagia as a clinical manifestation in the pandemic period vs. the prepandemic period, with an increase in more severe lesions in the pandemic period, has a statistical significance of 8% more newly diagnosed compared to the pre-pandemic period. Conclusion: The addressability of the patients during the COVID period was not affected in a drastic way in our study. We encountered a decrease in appointments in the age group 50–59 years and a decrease in patients with rural residence. In our study, we found an increase in cervicorrhagia as a reason for consultation in the pandemic period with a higher lesion degree, both on a pap smear and on a cervical biopsy.

In the present study. At first, some properties of r-fuzzy soft β-closed sets are introduced on fuzzy soft topological spaces based on the paper Aygunoglu et al. (Hacet. J. Math. Stat. 2014, 43, 193-208). Also, we define the closure and interior operators with respect to the classes of r-fuzzy soft β-closed and r-fuzzy soft β-open sets, and investigate some of their properties. In addition, the concept of r-fuzzy soft β-connected sets is introduced and characterized with help of fuzzy soft β-closure operators. Thereafter, some properties of a fuzzy soft β-continuity are studied. Furthermore, we introduce and study the concepts of fuzzy soft almost (weakly) β-continuous functions, which are weaker forms of a fuzzy soft β-continuity. Also, the relationships between these classes of functions are specified with the help of some illustrative examples. Finally, we explore new types of fuzzy soft functions called, fuzzy soft β-irresolute (strongly β-irresolute, β-irresolute open, β-irresolute closed and β-irresolute homeomorphism) functions, and discuss some properties of them. Also, we show that fuzzy soft strongly β-irresolute → fuzzy soft β-irresolute → fuzzy soft β-continuity, but the converse may not be true.

Proteomics research has become one of the most important topics in the fields of life science and natural science. At present, research on protein–protein interaction networks (PPINs) mainly focuses on detecting protein complexes or function modules. However, existing approaches are either ineffective or incomplete. In this paper, we investigate function module detection mechanisms in PPIN, including open databases, existing detection algorithms and recent solutions. After that, we describe the proposed solution based on simplified swarm optimization (SSO) algorithm and gene ontology knowledge. The proposed solution implements SSO algorithm for clustering proteins with similar function, and imports biological gene ontology knowledge for further identifying function complexes and improving detection accuracy. Furthermore, we use four different categories of species dataset for experiment: Fruitfly, Mouse, Scere, and Human. The testing and analysis result show that the proposed solution is feasible, efficient and could achieve a higher accuracy of prediction than existing approaches.

Herein we present the biocatalysed preparation of mono-N-carbamate-protected precursor of antitumoral Nutlin-3a, through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane, using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl-, diethyl and dimethyl- carbonate. The reactions were conducted at different temperatures, reaction times and with variable co-solvent systems to evaluate the effect on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) conducting the reaction solventless at 75 °C.

Bicyclic peptides have attracted the interest of pharmaceutical companies because of their remarkable properties putting them on a new path in medicine. Their conformational rigidity that improves proteolytic stability, leads to rapid penetration into tissues via any possible route of administration and elimination, occurring by renal metabolism, is of great importance for people with a history of liver diseases. In addition, each ring can function independently, making them extremely versatile molecules for further optimization. In this paper we compared the potentiometric and spectroscopic properties studied by UV-Vis, MCD, and EPR, of four synthetic analogues of the bi-cyclic peptide c(PKKHP-c(CFWKTC)-PKKH). In particular we correlated the structural and spectral properties of complexes with coordinating abilities toward Cu(II) ions of MCL (Ac-PKKHPc(CFWKTC)PKKH-NH2) that contains the unbinding cycle and N- and C-terminal linear parts, with two histidine residues, one per part; two monocyclic ligands containing one histidine residue, both in the N-terminal position i.e., MCL2 (Ac-PKKHPc(CFWKTC)PKKS-NH2) and in the C-terminal position i.e., MCL3 (Ac-PKKSPc(CFWKTC)PKKH-NH2), respectively, and the linear structure LNL (Ac-PKKHPSFWKTSPKKH-NH2).

The combination of immunoPET—where an antibody (Ab) is labeled with an isotope for PET imaging—and radioimmunotherapy (RIT), using the same antibody with a therapeutic isotope, offers significant advantages in cancer management. ImmunoPET allows non-invasive imaging of antigen expression, which aids in patient selection for a subsequent radioimmunotherapy. It also facilitates the assessment of tumor response to therapy, allowing for treatment adjustments if necessary. In addition, immunoPET provides critical pharmacokinetic data, including antibody biodistribution and clearance rates, which are essential for dosimetry calculations and treatment protocol optimization. There are still challenges to overcome. Identifying appropriate target antigens that are selectively expressed on cancer cells while minimally expressed on normal tissues remains a major hurdle to reduce off-target toxicity. In addition, it is critical to optimize the pharmacokinetics of radio-labeled antibodies to maximize tumor uptake and minimize normal tissue uptake, particularly in vital organs such as the liver and kidney. This approach offers the potential for targeted and personalized cancer therapy with reduced systemic toxicity by exploiting the specificity of monoclonal antibodies and the cytotoxic effects of radiation. However, further research is needed to address remaining challenges and to optimize these technologies for clinical use.

The lymphatic system of the brain meninges and head plays a crucial role in the clearance of amyloid-β protein (Aβ), a peptide thought to be pathogenic in Alzheimer’s disease (AD), from the brain. The development of methods to modulate lymphatic clearance of Aβ from the brain coild be a revolutionary step in the therapy of AD. The opening of the blood-brain barrier (OBBB) by focused ultrasound is considered as a possible tool for stimulation of clearance of Aβ from the brain of humans and animals. Here, we propose an alternative method of non-invasive music-induced OBBB that is accompanied by the activation of clearance of fluorescent Aβ (Fαβ) from the mouse brain. Using confocal imaging, fluorescence microscopy and magnetic resonance tomography, we clearly demonstrate that OBBB by music stimulates the movement of Fαβ and Omniscan in the cerebrospinal fluid and lymphatic clearance of Fαβ from the brain. We propose the extended detrended fluctuation analysis (EDFA) as a promising method for the identification of OBBB markers in the electroencephalographic (EEG) patterns. These pilot results suggest that music-induced OBBB and the EDFA analysis of EEG can be a non-invasive, low cost, labelling free, clinical perspective and completely new approach for the treatment and monitoring of AD.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ soluble protofibrils was approved by US FDA for AD therapy thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms are widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7- Aβ) and the α4β2 nicotinic acetylcholine receptor.

Polystyrene as a thin film on arbitrary substrates or pellets form defective graphene films or powders that can be dispersed in water and organic solvents. The materials were characterized by visible absorption, Raman and X-ray photoelectron spectroscopy, electron and atomic force microscopy and electrochemistry. Raman spectra of these materials show the presence of the expected 2D, G and D peaks at 2750, 1590 and 1350 cm^-1, respectively. The relative intensity of the G vs. the D peak is taken as a quantitative indicator of the density of defects in the G layer.

Quite a number of cottonseed varieties are existed. The seeds of each variety produce a different amount of gossypol as a natural toxic compound. The increased interest in this natural product and its toxic effects were enhanced the demand for establishing simple silica-gel-based methods for its isolation, purification, and characterization. Historically, silica gel plays a significant role in isolation and purification of many different natural products. Silica gel is variants and can intro-duce a lab, simple tool for tracking a compound in certain plants during its purification process. In this study, gossypol was isolated and purified in the form of yellow crystals as gossypol acetic ac-id. Several methods and tools were used for its characterization including TLC, preparative TLC, silica gel column, UV/IR spectrophotometer and HPLC (Robust spherical silica gel). A compara-tive study between its amounts in both Egyptian and Chinese varieties were performed. Under the experimental condition, the Egyptian cottonseeds contain 8.705 gm/kg, while the Chinese contains 5.395 gm/kg. Thin Layer Chromatography (TLC) had been flourished the science of the phytochemistry and still popular till nowadays and is recommended for fast, accurate, and inex-pensive evaluation and quantification of gossypol. It is recommended to isolate and purify gossy-pol as gossypol acetic acid using optimized combined methods used in this study. Using Silica gel different protocols will assist and facilitate the parallel comparison and save the compact column from any unexpected contaminants during the purification steps. During each step the silica gel itself could be simply removed by paper filtration.

Abstract: Currently, antibodies are major therapeutic modalities in biopharmaceutical research and development. Because of required high dose for certain clinical applications, antibodies are formulated at high protein concentration for convenience of administration, shipping and storage. We will describe the inter-molecular interactions that can occur in such a crowded environment of high protein concentration. Two types of repulsive interactions, i.e., electrostatic and excluded volume effects, and three types of attractive interactions, i.e., hydrophobic, electrostatic and cross-linking, need to be considered in such a crowded environments. We then show consequences of such inter-molecular interactions, leading to high viscosity, opalescence and phase separation of antibody solutions. Co-solvents are used to control the stability, structure and molecular interactions and thereby to alleviate these solution problems. Among various co-solvents, arginine has been extensively used to suppress protein-protein interactions at high protein concentration. Arginine weakly but extensively interacts with aromatic/hydrophobic groups as well as charged groups on proteins, leading to effective suppression of viscosity, opalescence and phase separation of antibody solution.

This study was conducted to investigate the effect of supplementing different types of methionine (L and D-type) and its precursor (HMBi) on milk protein synthesis using immortalized bovine mammary epithelial cell line (MAC-T Cell); D-methionine (D-Met), L-methionine (L-met) and 2-hydroxy-4-methylthiobutanoic acid I (HMBi), an isopropyl ester of the hydroxy analogue precursor of methionine. The underlying mechanism of milk protein synthesis by adding D- and L-type amino acid as well as HMBi was elucidated through omics analysis to verify the metabolism pathway. Results showed that HMBi group showed the highest beta casein mRNA expression levels compared to D- and L-Met groups and highest medium protein although not different with the L-Met treatment. The observed upregulated (>2 protein expression vs. control) and downregulated (<0.5 protein expression vs. control) proteins in L-Met, D-Met and HMBi treated groups were: 39, 77; 46, 68; and 40, 78, respectively. Interestingly, based on protein pathway analysis, L-Met treated group stimulated the ATP synthesis, PI3 kinase and pyruvate metabolism. On the other hand, the D-Met group stimulated fructose-galactose metabolism, glycolysis pathway, PI3 kinase and pyruvate metabolism. And lastly HMBi-treated group stimulated pentose phosphate pathway and glycolysis pathway. Metabolite analysis revealed that L-Met treated group resulted in the increase in 11 metabolites. On the other hand, D-Met treated group showed increase in 7 metabolites and decreased of uridine monophosphate (UMP). HMBi supplementation caused increases of 3 metabolites and decreased of UMP and N-acetyl-L-glutamate Addition of different isoforms of Met stimulated the production of intermediate metabolites for energy production. Addition of L-Met stimulated the production of energy metabolites such as pyruvate, malate, and fumarate, well-known as intermediates of Krebs cycle. On the other hand, HMBi supplementation resulted in increases of energy metabolite glucose 1-phosphate and 6-phosphogluconate. Results showed that HMBi-treated group exhibited highest expression of β-casein mRNA expression by stimulating proteins and metabolites as well as protein and metabolic pathways involved in protein and energy synthesis. As a result, HMBi-treated group resulted in highest protein concentration but not significantly different with L-Met. Both the D- and L-isoforms has considerably the same medium protein concentration and β-casein mRNA expression higher than the control. So, D- and L-Met isoforms can be used alternatively without any significant change in protein synthesis efficiency in bovine mammary epithelial cells.

A previous report showed that the urine output of HPLBII-P in patients with diabetes mellitus and SARS-Cov-2 infection was increased as a sign of glomerular dysfunction. . The aim of this report was to investigate the relation of urine output of HPLBII-P to diabetes mellitus in two large community-based elderly populations i.e. the ULSAM and PIVUS cohorts. Methods HPLBII-P was measured by ELISA in the urine of a community-based cohort of 839 men (ULSAM) collected at 77 years of age and in urine of a community-based cohort of 75-year-old men, n=387, and women, n=401 (PIVUS). KIM-1, NGAL and Albumin were measured in urine and Cathepsin S and Cystatin C in serum. Results HPLBII-P was significantly raised among males with diabetes in the ULSAM (p

Directed energy deposition (DED) parameters were determined for near-β alloy Ti-55511 by employing statistical design of experiments (DOE) methods. Parameters resulting in fully dense freeform deposits were identified using two sequential DOEs. Single laser tracks were printed with several laser power, traverse rate, and powder feed rate settings in an initial DOE to identify promising build parameters. Capture efficiency and effective deposition rate were used to characterize and rank the single track deposits. The best parameters were then used to print solid cube with various X-Y and Z-overlaps (different hatch spacing, HS, and layer thickness, ZS) in a second DOE. Suitable deposition parameters were selected based on cube density and microstructure and were used to fabricate larger tensile samples for mechanical testing. Multiple parameter sets were found to provide dense Ti-55511 deposits with acceptable mechanical properties and parametric models showed statistical significance.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

As humans age, aberrancies in several signaling pathways occur. In the aging population, some patients display abnormal bone morphogenetic protein (BMP) signaling. This can lead to osteoporosis (OP), a debilitating bone disorder caused by an imbalance between osteoblasts and osteoclasts. In 2002, the Food and Drug Administration (FDA) approved usage of recombinant human BMP-2 (rhBMP-2) during spinal fusion surgery as it is crucial for bone formation. However, complications have been reported with rhBMP-2 and primary osteoblasts isolated from OP patients are unresponsive to BMP-2. While patient samples are available, previous medical history may alter results. Therefore, C57BL/6 mice, an aging model that displays aberrant BMP-signaling, can be utilized to investigate OP and aging. We show that BMP receptor type Ia (BMPRIa) is upregulated in the bone marrow stromal cells (BMSCs) of 15-month mice similar to previous data. We show that a conjugation between BMP-2 and Quantum Dots (QDot®s) effectively binds to BMPRIa and can investigate BMP-2 activity. After incubating BMSCs with methyl-β-cyclodextrin (MβCD), BMP-signaling is restored in 15-month mice as shown by western blotting and the von Kossa assay. MβCD may be used to rescue BMPRIa and the BMP-signaling pathway can be utilized by future therapeutics to treat OP.

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy of AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with the potential for the treatment of AD. Previously, we demonstrated that TBN markedly improved cognitive functions and reduced Aβ, APP, BACE 1 and hyperphosphorylated tau levels in 3 × Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition still unclear. In this study, we employed the APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN on the Aβ reduction. Our results indicated that TBN significantly alleviated cognitive impairment and reduced Aβ depositions in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway and inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, as well as decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely via reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.

Abstract: Peptide pools composed of short amino acid sequences have proven to be versatile tools in various research areas and clinical applications. They are powerful tools for epitope mapping, immunotherapy, and vaccine development. Their importance lies in their ability to map complex protein structures, enabling a comprehensive understanding of immune responses and facilitating the identification of potential therapeutic agents. The application of peptide pools also extends to the field of personalized medicine, offering tailored solutions for diseases such as cancer and infectious diseases. Peptide pools are complex mixtures of immunostimulatory antigens primarily intended for T-cell stimulation. They are commercially available in many different compositions and variants. However, unlike other reagents that consist of only one or a few compounds, peptide pools are highly complex products with limited stability. This makes their quality control a major challenge. Quantitative peptide analysis usually requires sophisticated methods, in most cases isotope-labeled standards and reference materials. None of these are routinely available for these products. Synthesis and purification of all labeled peptides might be required. Usually, this approach would be prohibitively laborious and expensive. Therefore, an approach is needed to provide a practical and feasible method for quality control of peptide pools. With insufficient quality control, the use of such products could lead to incorrect experimental results, which would worsen the well-known reproducibility crisis in the biomedical sciences. Here we propose the use of ultra-high performance liquid chromatography (UHPLC) with two detectors, a standard UV detector (at 214 nm) for quantitative analysis and a high-resolution mass spectrometer (HRMS) for identity confirmation. To be cost-efficient and fast, quantification and identification are performed in one chromatographic run. An optimized protocol is shown, and different peak integration methods are compared and discussed. This work was performed using a peptide pool known as CEF, which consists of 32 peptides derived from cytomegalovirus (CMV), Epstein-Barr virus (EBV) and influenza virus, ranging from 8 to 12 amino acids in length.

Background In this study we investigated in detail the role of cannabidiol (CBD), Beta-caryophyllene (BC), or their combinations in diabetic peripheral neuropathy (DN). The key factors that contribute to DN include mitochondrial dysfunction, inflammation, and oxidative stress. Methods Briefly, Streptozotocin (STZ) (55 mg/kg) was injected intraperitoneally to induce DN in Sprague Dawley rats and performed procedures including Randall Sellito Calipers, Von Frey Aesthesiometer, hot plate, and cold plate methods to determine mechanical and thermal hyperalgesia in vivo. The blood flow to the nerves was assessed by using the Laser Doppler device. Schwann cells were exposed to high glucose (HG) at a dose of 30 mM to induce hyperglycemia and DCFDA, JC1 & Mitosox staining were done to determine mitochondrial membrane potential, reactive oxygen species and mitochondrial superoxides in-vitro. The rats were administered i.p with BC (30mg/kg), CBD (15mg/kg), or combination while Schwann cells were treated with 3.65 µM CBD, 75 µM BC, or combination to assess their role in DN amelioration. Results Our results revealed that exposure to BC and CBD diminished HG-induced hyperglycemia in Schwann cells, in part, through reducing mitochondrial membrane potential, reactive oxygen species and mitochondrial superoxides. Further, BC and CBD combination treatment in-vivo could prevent the deterioration of mitochondrial quality control system by promoting autophagy and mitochondrial biogenesis while improving blood flow. CBD and BC treatments also reduced pain hypersensitivity to hyperalgesia and allodynia with increased antioxidant and anti-inflammatory action in diabetic rats. These in vivo effects were attributed to significant upregulation of AMPK, SIRT3, Nrf2, PINK1, PARKIN, LC3B, Beclin1 and TFAM functions while downregulation of NLRP3 inflammasome, NFκB, COX2 and p62 activity was noted as determined by western blotting. Conclusion the present studies demonstrated that STZ & HG induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. We find, for the first time, that CBD and BC combination ameliorate DN via modulating the mitochondrial quality control system.

The role of foods is shifting from focusing on the provision of energy and basic nutrients to also include bioactive compounds that prevent the development of chronic age-related diseases. Mi-croalgae offer a source of nutritional compounds with important health effects, and have the po-tential for production of health-promoting products, without increasing agricultural land use and negatively impacting the environment. Here we investigate the health effects of microalgal ex-tracts with high levels of the colourless carotenoid phytoene. Phytoene is widely available from dietary sources and can be detected across different tissues in the human body. However, it is usually regarded as a precursor for the synthesis of other carotenoids, rather than a bioactive molecule. We utilised the model organism C. elegans to show that phytoene-rich extracts from Chlorella sorokiniana and Dunaliella bardawil have anti-ageing properties. The extracts protect against oxidative damage and amyloid-β42 proteotoxicity (a major pathology of Alzheimer's disease), and extends lifespan. We show that pure phytoene also has these anti-ageing effects, suggesting that phytoene is a bioactive molecule with positive effects on ageing and longevity.

Secure development is a proactive approach to cyber security. Rather than building a technological solution and then securing it in retrospect, secure development strives to embed good security practices throughout the development process and thereby reduces risk. Unfortunately, evidence suggests secure development is complex, costly, and limited in practice. This article therefore introduces security-focused prototyping as a natural precursor to secure development that embeds security at the beginning of the development process, can be used to discover domain specific security requirements, and can help organisations navigate the complexity of secure development such that the resources and commitment it requires are better understood. Two case studies–one considering the creation of a bespoke web platform and the other considering the application layer of an Internet of Things system–verify the potential of the approach and its ability to discover domain specific security requirements in particular. Future work could build on this work by conducting case studies to further verify the potential of security-focused prototyping and even investigate its capacity to be used as a tool capable of reducing a broader, socio-technical, kind of risk.

Alzheimer’s disease is associated with prion-like aggregation of the amyloid β (Aβ) peptide and the subsequent accumulation of misfolded neurotoxic aggregates in the brain. Therefore, it is critical to clearly identify the factors that trigger the cascade of Aβ misfolding and aggregation. Numerous studies have pointed out the association between microorganisms and their virulence factors and Alzheimer’s disease; however, their exact mechanisms of action remain unclear. Recently, we discovered a new pathogenic role of bacterial extracellular DNA, triggering the formation of misfolded Tau aggregates. In this study, we investigated the possible role of DNA extracted from different bacterial and eukaryotic cells in triggering Aβ aggregation in vitro. Interestingly, we found that the extracellular DNA of some, but not all, bacteria is an effective trigger of Aβ aggregation. Furthermore, the acceleration of Aβ nucleation and elongation can vary based on the concentration of the bacterial DNA and the bacterial strain from which this DNA had originated. Our findings suggest that bacterial extracellular DNA might play a previously overlooked role in the Aβ protein misfolding associated with Alzheimer’s disease pathogenesis. Moreover, it highlights a new mechanism of how distantly localized bacteria can remotely contribute to protein misfolding and diseases associated with this process. These findings might lead to the use of bacterial DNA as a novel therapeutic target for the prevention and treatment of Alzheimer’s disease.

This year marks the 20th anniversary of the discovery that proteins with various cellular functions can be temporarily immobilized in the nucleolus, a process known as nucleolar sequestration. This review reflects on the progress made to understand the physiological roles of nucleolar sequestration and the mechanisms involved in protein immobilization. We discuss how nucleolar sequestration consists of a highly choreographed amyloidogenic liquid-to-solid phase transition that converts the nucleolus into Amyloid bodies (A-bodies). The study of solid condensates A-bodies will offer unique perspectives on cellular assembly of membrane-less compartments and provide alternative insights on pathological amyloidogenesis involved in neurological disorders.

Alzheimer’s Disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, the latter termed cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) within the cerebrovasculature and its potential associations with CAA, gender, and ApoE4 genotype. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher colocalization of HS with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebral vasculature was detected in AD patients with severe CAA, suggesting a potential role in CAA development. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings shed light on the intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further exploring the underlying mechanisms may present novel therapeutic avenues for AD treatment.

Researchers are exploring solutions to meet the growing demand for protein due to the expected increase in global population by 2050. Interest in alternative protein sources like insects has risen, driven by concerns about environmental impact and the need for sustainable food production. This study aimed to develop and evaluate the physicochemical properties of soy protein-based burger enriched with insect protein from Alphitobius diaperinus. Three formulations were developed: a control (B0), and burgers with 5% (B5) and 10% (B10) insect protein - Whole Buffalo Powder (WBP). Results showed that adding insect protein decreased the burger analogue's pH. There was observed a clear trend of increasing total lipids and SFA, and decreasing MUFA and PUFA, as the WBP concentration increases from 0% to 10%. No significant differences with increasing WBP concentration in the protein content of the burger analogue, as well as the cooking yield, were noted. The WBP addition had a notable effect on the color change, especially decrease in brightness (L*). It was shown that as the WBP concentration increased, there were no significant differences in the texture profile of the burger analogues. The formulation with 5% WBP concentration was the most acceptable in sensory analysis.

We changed the symmetry of the Weak Force from SU(2) to the quaternion group $Q_8$, and found that spin spacetime separates into two complementary spaces: a spin polarization spacetime of even parity states, and a spin coherence space, in the $S^3$ hypersphere, of odd parity coherent states. Under the quaternion group, spin is a boson of spin 1 in free flight and a fermion of spin $\frac{1}{2}$ when measured. It immediately follows that neutrinos are not needed to balance spin and conserve energy in beta decay. Additionally, we find the boson electrons emitted in beta decay are odd to parity, leading to parity conservation even though the observed beta distribution is asymmetrical.

The main objective of this paper is to introduce a further extension of extended (p, q)-beta function by considering two Mittag-Leffler function in the kernel. We investigate various properties of this newly defined beta function such as integral representations, summation formulas and Mellin transform. We define extended beta distribution and its mean, variance and moment generating function with the help of extension of beta function. Also, we establish an extension of extended (p, q)-hypergeometric and (p, q)-confluent hypergeometric functions by using the extension of beta function. Various properties of newly defined extended hypergeometric and confluent hypergeometric functions such as integral representations, Mellin transformations, differentiation formulas, transformation and summation formulas are investigated.

The structures of recently discovered primarolides A and B suggest their non-enzymatic formation from a common 2-formylbenzophenone precursor. This hypothesis is based on the experimentally proven facile conversion of pestalone (also a 2-formyl-benzophenone) either into the isomeric lactone pestalalactone or the structurally related isoindolinone pestalachloride A. In a related fashion, the racemic isoindolinone natural product mariline A is supposed to biosynthetically originate from the corresponding keto-aldehyde and an aniline, as experimentally supported by model studies. Due to the close structural relationship with known systems, it appears highly probable that primarolides A and B were generated under the fermentation conditions from a massarinin-related 2-formylbenzophenone (proprimarolide) by reaction either with aniline or a nucleophilic catalyst, respectively. Suberoylanilide hydroxamic acid (SAHA), used as an additive during the fermentation, is supposed to act both as a source of aniline and as a nucleophilic catalyst.

Cercospora beticola Sacc. is an ascomycete pathogen that causes Cercospora leaf spot in sugar beets (Beta vulgaris L.) and other related crops. The disease symptoms are characterized by circular lesions with an ash-gray centre and dark brown to purple margins on the leaves. It can lead to significant yield losses if not effectively managed. This study aims to characterize and assess the impact of bacterial biological control agents against C. beticola. Following a dual-culture screening, 18 bacteria exhibiting over 50% inhibition were selected, with six of them demonstrating more than 80% control. Identification of the bacteria was carried out through sequencing of the16S rDNA, revealing potentially 12 species belonging to six genera including Bacillus which was represented by four species. Additionally, the bacteria underwent in-depth characterization of biochemical and molecular properties, as well as plant-growth promotion. PCR detection of genes responsible for producing antifungal metabolites revealed that 83%, 78%, 89%, and 56% of the selected bacteria possessed the bacillomycin, iturin, fengycin, and surfactin encoding genes, respectively. Infrared spectroscopy analysis confirmed the presence of lipopeptide structure in the bacteria supernatant filtrate. Subsequently, the bacteria were assessed for their effect on sugar beet plants in controlled conditions. The bacteria exhibited notable capabilities, promoting growth in both roots and shoots, resulting in significant increases in root length, weight, and shoot length. The field experiment with four bacterial candidates demonstrated good performance against C. beticola compared to difenoconazole fungicide. These bacteria played a significant role in disease control, achieving a maximum efficacy of 77.42%, slightly below the 88.51% efficacy attained by difenoconazole. Additional field trials are necessary to verify the protective and growth-promoting effects of these candidates, whether applied individually, combined in consortia, or integrated with chemical inputs in sugar beet crop production.

Fisheries and bottom seawater data were collected in July in 2022 and 2023 from 15 sampling stations in the Huanghe River Estuary and adjacent seas in China. The patterns of functional alpha- and beta-diversity of fish communities in this area and their relationship with environmental factors were studied using trait-based analysis. Five functional classifications, which included 16 functional traits, four functional alpha-diversity indices (functional richness, functional evenness, functional divergence, and community-weighted mean), three functional beta-diversity indices (functional beta-diversity and its turnover and nestedness components), and 14 bottom environmental factors were considered. The dominant traits of fish communities were: benthivorous feeding habits, small and front-facing mouths, high trophic level, demersal, anguilliform, low growth coefficient, medium resilience, low vulnerability, and adapted to warm temperate conditions. The dominant migration traits and types of fish eggs varied by year, and fish abundance was the main factor affecting the dominant traits of the communities. The results of multiple regression on distance matrices and variance partitioning analysis indicated that ammonia nitrogen content, total phosphorus content, and pH were the main environmental factors that affected fish functional diversity. The N/P ratio had an upward control effect on fish functional diversity. Our findings also revealed that high pH gradients and distant geographical distances can inhibit trait turnover in fish communities.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

We report on recent experimental results on β decay into self-conjugate (N=Z) nuclei with mass number 58≤A≤70. Super-allowed β decays from the Jπ=0+ ground state of a Z=N+2 parent nucleus are to the isobaric analogue state, through so-called Fermi transitions, and to Jπ=1+ states, by way of Gamow–Teller (GT) transitions. The operator of the latter decay is a generator of Wigner’s SU(4) algebra and as a consequence GT transitions obey selection rules associated with this symmetry. Since SU(4) is progressively broken with increasing A, mainly as a consequence of the spin–orbit interaction, this symmetry is not relevant for the nuclei considered here. We argue, however, that the pseudo-spin–orbit splitting can be small in nuclei with 58≤A≤70, in which case nuclear states exhibit an approximate pseudo-SU(4) symmetry. To test this conjecture, GT decay strength is calculated with use of a schematic Hamiltonian with pseudo-SU(4) symmetry. Some generic features of the GT β decay due to pseudo-SU(4) symmetry are pointed out. The experimentally observed GT strength indicates a restoration of pseudo-SU(4) symmetry for A=70.

Thalassemia is genetic blood disease cause by absence or decrease of one or more of the globin chain synthesis. Beta thalassemia is characterized by one or more mutations in beta globin gene. Absence or reduced amount the of beta globin chains cause ineffective erythropoiesis which leads to anemia. Beta thalassemia has been further divided into three main forms: Thalassemia minor/silent carrier, major and intermedia. More severe form is thalassemia major in which patients depend upon blood transfusion for survival and high level of iron occur as a consequence of consistent blood transfusion. Over loaded iron invokes the synthesis of reactive oxygen species that are toxic in redundancy and triggering the impairment to vascular, endocrine and hepatic system. Thalassemia can be diagnosed and detected through various laboratory tests such as blood smear, prenatal testing (genetic testing of amniotic fluid), DNA analysis (genetic testing) and complete blood count. Treatment of thalassemia intermedia is symptomatic but it can also be managed by splenectomy and folic supplementation. While thalassemia major can be treated by transplantation of bone marrow, regular transfusion of blood and iron chelation treatment, stimulation of fetal hemoglobin production, hematopoietic stem cell transplantation and gene therapy.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densi- ties and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on dierent set of true values. Some real data sets were employed to show the usefulness and exibility of the model which serves as generalization to many sub-models in the elds of engineering, medical, survival and reliability analysis.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densities and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on different set of true values. Some real data sets were employed to show the usefulness and flexibility of the model which serves as generalization to many sub-models in the field of engineering, medical, survival and reliability analysis.

A new generalization of extended beta function and its various properties, integral representations and distribution are given in this paper. In addition, we establish the generalization of extended hypergeometric and con uent hypergeometric functions using the newly extended beta function. The properties these extended and con uent hypergeometric functions such as integral representations, Mellin transformations, dif- ferentiation formulas, transformation and summation formulas are also investigated.

In this paper we introduce the concept of Nano Beta Closure, Nano Beta Interior and study the relationship between them also study some of their properties. Based on these notions we introduced the topological Approach to Decision Making and Its Application in the Medical Field" which describes the use of topological methods in decision-making, specifically through the utilization of nano beta closure and nano beta interior. These mathematical tools are applied in the medical field to improve diagnostic accuracy and aid in treatment planning. The authors demonstrate the effectiveness of this approach through a case study on the diagnosis of Chronic Kidney. The results show that the topological approach using nano beta closure and nano beta interior provides a reliable and accurate method for medical decision-making. Finally, we introduce a medical application for disease groups patients of with chronic kidney. To identify the main causative agent of kidney disease. where using this approach, the medical team can identify the specific areas of the kidney that are affected by the infection, as well as the extent of damage and any potential complications. This information is used to create an individualized treatment strategy that is customized to meet the specific requirements of the patient. and medical history. We write an algorithm that can be a helpful tool for doctors to utilize in diagnosing infection disease Chronic Kidney infections. By utilizing this approach, clinicians can provide accurate diagnoses, develop effective treatment plans, and ultimately improve patient outcomes. finally, we show that fractals hold significant importance in future nano topological generation of the human factor. Their unique properties and self-similar patterns offer insights into the complex organization of biological systems and provide a foundation for designing advanced Nanosystems.

With reference to Planck scale, Mach’s relation, increasing support for large scale cosmic anisotropy and preferred directions and by introducing two new parameters Gamma and Beta, right from the beginning of Planck scale, we make an attempt to estimate ordinary matter density ratio, dark matter density ratio, mass, radius, temperature, age and expansion velocity (from and about the baby universe in all directions). We would like suggest that, from the beginning of Planck scale, 1) Dark matter can be considered as a kind of cosmic foam responsible for formation of galaxies. 2) Cosmic angular velocity is directly proportional to squared cosmic temperature. 3) Ratio of critical temperature to actual temperature plays a heuristic role in understanding ordinary and dark matter density ratios. 4) Cosmic expansion velocity increases with decreasing total matter density ratio. 5) There is no need to consider dark energy for understanding cosmic acceleration.

The novel coronavirus pneumonia (COVID-19) is a contagious acute respiratory infectious disease whose causative agent has been demonstrated to be a novel virus of the coronavirus family, SARSCoV-2. A recent pre-print study has showed a heme attack on the 1-beta chain of hemoglobin by COVID19. Beta-thalassemia results of a default in the hemoglobin beta- chain synthesis. 1,5% global population are heterozygotes for this disease. In this study, by a multiple linear regression, we have analyzed the evolution of COVID-19 infection in three Italian regions (Puglia, Sardinia, Sicilia) with different beta-thalassemic prevalences, in order to search a link. The results have showed that betathalassemic heterozygote population prevalence is correlated to immunity against COVID-19, by a regression. This paper is only for academic discussion, the hypotheses and conclusions needs to be confirmed by further research .

Carbapenem antibiotics are the drug of choice for treating multidrug-resistant bacterial infections. Metallo-beta-lactamases (MBLs) are carbapenemase capable of hydrolyzing nearly all therapeutically available beta-lactam antibiotics. Consequently, a need to assess the frequency and phenotypic resistance phenomena of two MBL genes in diarrheal and urinary tract infections (UTIs). Samples were collected through a cross-sectional study, with MBLs genes detected via PCR. Two hundred twenty eight diarrheal bacteria were isolated from 240 samples. The most predominant pathogens were Escherichia coli (32%) and Klebsiella spp. (7%). Phenotypic resistance to amoxicillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 50.4%, 65.6%, 66.8%, 80.5%, 54.4%, 41.6%, 25.7%, 41.2%, 37.2%, and 42.9%, respectively.  Total 142 UTI pathogens were obtained from 150 urine samples, with Klebsiella spp. (39%) and Escherichia coli (24%) are the major pathogens. Phenotypic resistance to amoxycillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 93.7%, 75.0%, 91.5%, 93.7%, 88.0%, 72.5%, 13.6%, 44.4%, 71.1%, and 43%, respectively.  Twenty four diarrheal isolates carried either blaNDM-1 or blaVIM genes; the overall MBL gene prevalence was 10.5%. Thirty six UTI pathogens carried either blaNDM-1 or blaVIM genes (25.4%). Seven isolates carried both blaNDM-1 and blaVIM genes.  MBL genes exhibited a strong association with phenotypic carbapenem and other beta-lactam antibiotic resistance. Resistance to carbapenems requires active surveillance and stewardship.

The emergence of the coronavirus 19 (COVID-19) has posed a major challenge to healthcare systems worldwide, especially as COVID-19 mutations complicate the development of vaccines and antiviral drugs. Therefore, the search for natural products with broad anti-COVID-19 capabilities is an important option for the prevention and treatment of infectious diseases. Lectins, which are widely recognized as antiviral agents, could contribute to the development of anti-COVID-19 drugs. In this study, we evaluated the binding ability of a total of six lectins, including MVL from Microcystis viridis NIES-102, to the spike protein RBD of the original (wild) COVID-19 and it’s three mutants: alpha, delta, and omicron. As a result, two lectins, MVL from Microcystis viridis NIES-102 and jacalin from Artocarpus altilis, showed distinct binding ability to the RBDs of the four COVID-19 strains. The other lectins (DB1, ConA, PHA-M and CSL3) did not show any binding ability. Although the glycan specificities of the two lectins, MVL and Jacalin, were different, they showed the same affinity for the RBDs of the four COVID-19 strains, i.e., alpha &gt; delta &gt; original &gt; omicron. The verification of glycan-specific inhibition revealed that jacalin binds to RBDs by glycan-specific recognition, whereas MVL binds to RBDs by protein-protein interactions in addition to glycan-specific recognition.

The stock beta coefficient literature extensively discusses the proper methods for the estimation of beta as well as its use in asset valuation. However, there are relatively few references with respect to the appropriate time horizon that investors should utilize when evaluating the risk-return relationship of a stock. We examine the appropriate time horizon for beta estimation differentiating our results by sector according to the Industry Classification Benchmark. We employ data from the NYSE and we estimate varying lengths of beta employing data from 30 to 250 trading days. The constructed beta series is then examined for the presence of breaks using the endogenous structural break literature. Results show evidence against the use of betas that employ more than 90 trading days of data provisional to the sector under study.

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

The manuscript presents the comprehensive integrative theory of the etiology and pathogenesis of Alzheimer’s disease - the amyloid degradation toxicity hypothesis - and describes the logic that underlies it.The analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies suggest that AD diagnosis is associated with higher cellular uptake of beta-amyloid. Uptake of beta-amyloid by cells is needed for its cytotoxicity, so the uptake rate should correlate with the rate of neurodegeneration. Also, the initial step in forming extracellular aggregates cannot occur in the interstitial fluid due to the extremely low concentration of beta-amyloid but can occur intralysosomally. Therefore, the density of extracellular aggregates should positively correlate with the rate of cellular amyloid uptake. The model, which considers that both cytotoxicity and aggregation of beta-amyloid are defined by cellular uptake, successfully reproduces the probability distribution of AD diagnosis in the population. Cellular uptake of beta-amyloid is mediated by endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage. Lysosomal permeabilization explains ion disturbances, such as an accumulation of intracellular calcium, caused by cell exposure to extracellular beta-amyloid. Some amyloid fragments, produced from beta-amyloid by lysosomal proteases, can form membrane channels in lysosomal membranes, which are large enough to leak cathepsins to the cytoplasm. Appearance of proteases in the cytoplasm results in necrosis and/or initiation of apoptosis. If the cell survives, the damage of lysosomes leads to autophagy failure and slow recycling of mitochondria, promoting the production of reactive oxygen species and potentiating cell damage.Considering the above, the integrative theory of AD etiology and pathogenesis can be formulated. The etiology of AD is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization by giant membrane channels, which leak lysosomal proteases into the cytoplasm. The correlation between the density of amyloid aggregates and the probability of AD appears because the intensity of cellular uptake defines both aggregation rates in vivo and cytotoxicity of beta-amyloid.The amyloid degradation toxicity hypothesis is the integrative theory of Alzheimer’s disease (AD). It successfully interprets multiple phenomena and paradoxes associated with AD pathobiology at various levels, from molecular and cellular to biomarkers. The hypothesis explains the limitations of currently used biomarkers of AD and proposes etiology-related parameters. These parameters could be measured in humans and become novel diagnostic and prognostic clinical tools. Based on the proposed framework, we foresee the development of effective medications to treat, stall the progression of, or prevent disease development.

Amyloids are fibrillar protein aggregates that are associated with diseases such as Alzheimer’s disease, Parkinson’s disease, type II diabetes and Creutzfeldt–Jakob disease. The process of amyloid aggregation involves three pathological protein transformations; from natively-folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow surface-induced (including microbially-induced) HEN pathways. Furthermore, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively-folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions including replacement therapies.

Abnormal filamentous aggregates formed by tangled tau protein turn out to be classic amyloid fibrils, meeting all criteria defined under the fuzzy oil drop model in the context of amyloid characterization. The model recognizes amyloids as linear structures where local hydrophobicity minima and maxima propagate in an alternating manner along the fibril’s long axis. This distribution of hydrophobicity differs greatly from the classic monocentric hydrophobic core observed in globular proteins. Rather than becoming a globule, the amyloid instead forms a ribbonlike (or cylindrical) structure, which can be thought of as a distorted spherical micelle, which in limit form appears to be the ribbon-like micelle.

Acid proteins capable of nucleating Ca2+ and displaying aggregation capacity play key roles in the formation of calcium carbonate biominerals. EF-hands are among the largest Ca2+-binding motif in proteins. Gad m 1, an Atlantic cod β-parvalbumin isoform, is a monomeric EF-hand protein that acts as a Ca2+ buffer in fish muscle and is able to form amyloids under acidic conditions. Since nucleating Ca2+ protein have a propensity to form extended β-strand structures, we wondered whether amyloid assemblies of a protein containing refolded EF-hand motifs were able to influence the in vitro calcium carbonate crystallization. Here we have used the Gad m 1 chain as model to generate monomeric and amyloid assemblies and analyze their effect on in vitro calcite formation. We found that only amyloid assemblies alter calcite morphology.

Vaccination is one of the most effective methods for preventing morbidity and mortality from COVID-19. Vaccine hesitancy has led to a decrease in vaccine uptake; driven by misinformation, fear, and perceptions of vaccine safety. Whole inactivated vaccines have been used in one-fifth of the vaccine recipients in Africa, however there is limited real-world data on their safety. We evaluated the reported side effects and factors associated with reported side effects following vaccination with whole inactivated COVID-19 vaccines - BBiBP-CorV (Sinopharm) and CoronaVac (Sinovac). A quantitative survey evaluating attitudes and side effects from vaccination was administered to 1016 adults presenting at vaccination centers. Two follow-up telephone interviews were conducted to determine side effects after the first and second vaccination dose. Overall, the vaccine was well tolerated; 26.0% and 14.4% reported side effects after the first and second dose respectively. The most frequent local and systemic side effects were pain at the injection site and headaches respectively. Most symptoms were mild, and no participants re-quired hospitalization. Participants who perceived COVID-19 vaccines as safe or had a personal COVID-19 experience were significantly less likely to report side effects. Our findings provide data on the safety and tolerability of whole inactivated COVID-19 vaccines in an African population, providing the necessary data to create effective strategies to increase vaccination and support vaccination campaigns.

Using the method of the beta function, Sun has recently evaluated some series of the type $\sum_{k=0}^{\infty}(ak+b)x^k/\binom{mk}{nk}$. By factorization of the polynomial $t^{m-n}(1-t)^n-x$, we will give a general method to find new $\pi$-series.

This study aimed to evaluate cell therapy with human neural precursor cells (hNPCs) in diabetic retinopathy (DR) Wistar rats, induced to diabetes by intraperitoneal injection with streptozotocin. Wharton's Jelly Mesenchymal stem cells (WJ-MSCs) were isolated, expanded, and seeded onto a biopolymer substrate without growth factors to develop neurospheres to obtain the hNPCs, characterized by immunocytochemistry. The animals were divided into three groups; non-diabetic (ND) n = four; diabetic without treatment (DM) n = nine; and diabetic with cell therapy (DM + hNPCs) n = nine. After eight weeks of diabetes induction and verified DR, intravitreal injection of hNPCs (1 x 106 cel/µL) was performed in the DM + hNPCs group. Optical Coherence Tomography (OCT) and Electroretinography (ERG) evaluations were done before and after diabetes induction and after cell therapy. Eye enucleation occurred four weeks after treatment for the histopathological and immunohistochemistry analyses. In the treated group, there was the repair of the retinal structures and their arrangements. hNPCs increased the thickness of neuroretina layers, especially in the ganglion cell and photoreceptor layers. The results indicate that hNPCs reduced DR progression by a neuroprotective effect and promoted retinal repair, making them potential candidates for regeneration of the neuroretinal tissue.

The apicomplexan parasite, Sarcocystis neurona causes the degenerative neurological equine protozoal myeloencephalitis (EPM) disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions such as host cell invasion, cell cycle progression and host immune responses evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. Further, three-dimensional (3D) homology models for selected S. neurona putative PKs were constructed and evaluated for inhibitor docking. We identified 92 putative PKs clustering within the AGC, CAMK, CK1, CMGC, STE, TKL, aPK and OPK groups. Although containing the universally conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC, but contained the six apicomplexan conserved CDPKs (CAMK group). The OPK group was represented by ROPKs 19A, 27, 30, 33, 35 and 37, but was devoid of the virulence-associated ROPKs 5, 6, 18 and 38. Two out of the three S. neurona CK1 enzymes had high sequence similarities to T. gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Docking of four inhibitors onto homology models of putative ROP27 and PKA indicated that inhibition of S. neurona PKs is feasible, but needs to be experimentally tested. The essentiality of apicomplexan PKs makes the elucidation of S. neurona kinome a key milestone for development of novel therapeutics for EPM.

The acute phase protein Serum Amyloid A (SAA) is synthesised by the liver in response to inflammatory stimuli. Previous studies have revealed that SAA may be a better predictive marker for the course of inflammatory bowel disease (IBD) compared to C-reactive protein (CRP). Hence, this retrospective monocentric study evaluated whether SAA correlates with biomarkers like faecal calprotectin (FC), CRP, the Neutrophil to Lymphocyte ratio (NLR) and clinical disease activity of IBD patients. Serum samples from the IBD outpatient clinic of the University Hospital Heidelberg were analysed for their SAA concentrations if a FC concentration measurement was available from 14 days before or after collection of the serum sample. 306 serum samples from 265 patients (166 with Crohn’s disease, 91 with ulcerative colitis, 8 with IBD unclassified) met the inclusion criteria. There was a significant positive correlation between SAA and FC, CRP, the NLR and the Simple Clinical Colitis Activity Index. The cut-off for SAA serum concentration at 4.55 mg/l achieved a sensitivity of 57.5% and a specificity of 69.7% for the detection of active inflammation in IBD. SAA may be used as an additional biomarker in the disease monitoring strategy of IBD patients, especially in patients with low CRP concentrations.

Rice prolamins are categorized into three groups by molecular size (10, 13, or 16 kDa), while the 13 kDa prolamins are assigned to four subgroups (Pro13a-I, Pro13a-II, Pro13b-I, and Pro13b-II) based on cysteine residue content. Here, we generated four knockout strains of rice using CRISPR-Cas9, each of which demonstrated selectively reduced expression of specific subgroups of the 13 kDa prolamins. These four mutant rice lines also demonstrated compensatory expression of glutelins and non-targeted prolamins, which resulted in low grain weight, altered starch content and atypically-shaped starch granules and protein bodies. Transcriptome analysis identified 746 transcripts that were differentially expressed in the mutant rice lines during development. These transcripts played roles primarily in RNA processing, protein synthesis, stress response, and transport. After selective suppression/knockout of genes in the Pro13a-I subgroup, compensatory upregulation of genes in the Pro13a-II and Pro13b-I/II subgroups was observed. Compensatory expression of 9 ER stress and 17 transcription factor genes was also observed in mutant rice in which expression of 13 kDa prolamin genes was suppressed. Our results provide valuable insight into the regulatory mechanisms underlying rice seed development and the specific roles played by 13 kDa rice prolamins and their target genes.

The global food production system faces several challenges, including significant environmental impacts due to traditional agricultural practices. The rising demands of consumers for food products that are safe, healthy, and have animal welfare standards have led to an increased interest in alternative proteins and the development of the cellular agriculture field. Within this innovative field, precision fermentation emerges as a promising technological solution to produce proteins with reduced ecological footprints. This review provides a summary of the environmental impacts related to the current global food production, and explore how precision fermentation can contribute to address these issues. Additionally, we will report on the main animal-derived proteins produced by precision fermentation, with a particular focus on those used in the food and nutraceutical industries. The general principles of precision fermentation will be explained, including strain and bioprocess optimization. Examples of efficient recombinant protein production by bacteria and yeasts, such as milk proteins, egg-white proteins, structural and flavoring proteins, will also be addressed, along with case examples of companies producing these recombinant proteins in a commercial scale. Through these examples, we will explore how precision fermentation supports sustainable food production and holds the potential for significant innovations in the sector.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process disrupted in preeclampsia, characterized by elevated vascular resistance, re-duced utero-placental blood flow and intrauterine growth restriction. This study investigated PP13’s role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries isolated from both pregnant and non-pregnant women were precontracted with the thromboxane analogue U46619, and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated using specific inhibitors for ni-tric oxide synthase (L-NAME+LNNA at 10-4 M) and guanylate cyclase (ODQ at 10-5 M). Results showed PP13 induced vasodilation in uterine arteries but not in subcutaneous arteries. Ad-ditionally, PP13 counteract U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on activa-tion of the Nitric oxide-cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine ar-teries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest PP13 may be a promising candidate for improving utero-placental blood flow in condi-tions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia.

Dengue virus is a global health problem most prevalent in tropical and subtropical regions. However, after the approval of two vaccines, Dengvaxia, TV003/TV005 of Takeda, for its prevention, problems were reported, like enhanced risks of infection or less efficiency of protection. Since then, more struggles have been in demand for the development of better vaccines. Here, we conducted a new design through an in-silico strategy. Initially, epitopes were chosen based on their antigenicity, immunogenicity, and binding affinity with MHC molecule, while excluded with allergenicity, toxicity and potential risk of antibody dependent enhancement. Subsequently, a core antigen was constructed with selected epitopes and linked with distinct adjuvant proteins to achieve three candidate vaccines, PSDV-1~3. PSDV-2 was chosen for further validation based on their advantage in physicochemical and structural properties. With a panel of simulations, this artificial protein showed tight binding with pattern recognition receptors, good stability, robust immune induction, and ultimately was confirmed as a high quality vaccine candidate. The plasmid for its recombinant expression was then designed accordingly. With our new design, one more choice was obtained for the effective protection from Dengue virus. Further experimental validations are still require to confirm it protection capacity and safety.

Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological ac-tivities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose the cells were treated with UA and/or TGF-β1 for 24 hours. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility and up-regulated expression of b3 integrin and fibronectin. These typical for epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated in HG expression of TGF-β receptors and activation of TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a po-tential therapeutic agent in podocytopathies.

Proteins need to be located in appropriate spatiotemporal contexts to carry out their diverse biological functions. Mislocalized proteins may lead to a broad range of diseases, such as cancer and Alzheimer’s disease. Knowing where a target protein resides within a cell will give insights into tailored drug design for a disease. As the gold validation standard, the conventional wet lab uses fluorescent microscopy imaging, immunoelectron microscopy, and fluorescent biomarker tags for protein subcellular location identification. However, the booming era of proteomics and high-throughput sequencing generates tons of newly discovered proteins, making protein subcel-lular localization by wet-lab experiments a mission impossible. To tackle this concern, in the past decades, artificial intelligence (AI) and machine learning (ML), especially deep learning methods, have made significant progress in this research area. In this article, we review the latest advances in AI-based method development in three typical types of approaches, including sequence-based, knowledge-based, and image-based methods. We also elaborately discuss existing challenges and future directions in AI-based method development in this research field.

In this study, we aim to evaluate how cyclodextrin molecules affect the hydrophilicity and selec-tivity of PVDF membrane. Herein, we prepared PVDF-PVP(1-x) β-CDx membranes, with x rang-ing from 0 to 1 wt%. The membranes were deeply characterized by means of X-ray diffraction (XRD), attenuated total reflectance infrared (ATR-IR), Raman spectroscopies, Thermal gravimet-ric analysis (TGA), Contact angle measurement (CA), scanning electron microscopy (SEM) and atomic force microscopy (AFM). The study unequivocally demonstrates the effectiveness of the addition of β-CD molecules on membranes' structural, morphological, and dielectric properties. Adding 0.25wt% β-CD enhanced hydrophilicity, with CA decreasing from 72.6° to 56° and roughness decreasing from 81 to 29 nm. The PVDF-PVP(1-x) β-CDx membranes were then fully characterized using electrochemical impedance spectroscopy (EIS) to determine their dielectric properties, which clearly showed that the presence of β-CD induced polarization of the mem-brane. The separation of various dyes with different sizes and charges was utilized. These dyes included methylene blue (MB, positive, 0.504 nm), methyl red (MR, neutral, 0.487 nm), rose Bengal (RB, negative, 0.588 nm), and brilliant blue (BB, negative, 0.798 nm). Based on our re-search, we found that the membrane's selectivity is determined by both exclusion factors (such as size and dielectric properties) and inclusion inside the β-CD cage. We found that using alpha-CD instead of beta-CD led to the disappearance of dye inclusion. These findings strongly sug-gest that β-CD molecules can be a viable solution for dye removal from wastewater.

While vaccines are a well-established method of controlling the spread of infectious diseases, vaccine hesitancy jeopardizes curbing the spread of COVID-19. Through the Vaccine Information Network (VIN), this study explored barriers and motivators to COVID-19 vaccine uptake. We conducted 18 focus group discussions with male and female community members, stratified by country, age group, and—for Zimbabwe only—by HIV status. Participants’ median age across both countries was 40 years (interquartile range of 22–40) and most (65.9%) were female. We conceptualized the key themes within the World Health Organization’s Strategic Advisory Group of Experts on Immunization (SAGE) 3Cs (convenience, confidence, complacency) vaccine hesitancy model. Barriers to vaccine uptake—lack of convenience, low confidence, and high complacency—included inaccessibility of vaccines and vaccination sites, vaccine safety and development concerns, and disbelief in COVID-19’s existence. Motivators to vaccine uptake—convenience, confidence and low complacency—included accessibility of vaccination sites, user-friendly registration processes, trust in governments and vaccines, fear of dying from COVID-19 and knowing someone who had died or become infected with COVID-19. Overall, vaccine hesitancy in South Africa and Zimbabwe was influenced by inconvenience, a lack of confidence, and high complacency around COVID-19 vaccines.

A precise understanding of the genes and associated genomes of SARS-CoV2 is important for various reasons such as discovering origin of the virus and virulence and so on. A thorough descriptive understanding of the SARS-CoV2 genomes and other coronavirus of the beta-coronavirus genus is primarily important. In this article, a set of ten genomes of four CoVs and their associated genes are considered for this present study. A spatial representations of nucleotide bases including purine-pyrimidine representations of the different genes of the corresponding genomes are quantified using Hurst exponent, Shannon entropy and density estimation of different nucleotides including GC content, in order to draw a comparison and contrast among the ten genomes of different types of CoVs which include MERS, SARS-CoV, HKU1 (Human Coronavirus) and associated their genes.

The criteria of “Distinctness, Uniformity and Stability” as well as a high "overall quality index” are used to register the Italian modern varieties to the national register. Differently, local conservation varieties can be certified under different EU Directives having, as overall objective, the preservation of biodiversity and the containment of genetic erosion. In recent years, products derived from an-cient grains are perceived to be healthier and more sustainable by consumer, especially in Italy, with consequent higher market prices. Ancient tetraploid wheat varieties registered in the national reg-ister of conservation varieties are 28, 24 of which are Sicilian. They are supposed to have a wide genetic variability compared to modern ones, making them vulnerable of fraud because they are difficult to trace. It is therefore important to have tools able to discriminate the autochthonous Si-cilian varieties. This can be done by gluten proteins composition, which also gives information on the technological properties of derived products. Fifty-one accessions belonging to 22 ancient va-rieties of Sicilian tetraploid (mostly durum) wheat were analyzed. Although a wide intra-accession and intra-varietal variability was assessed, the gliadin pattern of bulks of seeds belonging to each variety was discriminatory. Moreover, differences in technological attitudes were found between landraces. This paves the way to use gluten protein patterns for traceability allowing local farmers and producers to valorize their products and assure consumers about the transparency of the entire supply chain.

TMEM16A is a Ca2+-activated Cl- channel expressed in various species and tissues. In mammalian skeletal muscle precursors, the activity of these channels is still poorly investigated. Here, we characterized TMEM16A channels and investigated if the pharmacological activation of Piezo1 channels could modulate the TMEM16A currents in mouse myogenic precursors. Whole-cell patch-clamp recordings combined with the pharmacological agents Ani9, T16inh-A01 and Yoda1 were used to characterize TMEM16A-mediated currents and the possible modulatory effect of Piezo1 activity on TMEM16A channels. Western blot analysis was also carried out to confirm the expression of TMEM16A and Piezo1 channel proteins. We found that TMEM16A channels were functionally expressed in fusion-competent mouse myogenic precursors. The pharmacological blockage of TMEM16A inhibited myocyte fusion into myotubes. Moreover, the specific Piezo1 antagonist Yoda1 positively regulated TMEM16A currents. The findings demonstrate, for the first time, a sarcolemmal TMEM16A channel activity and its involvement at the early stage of mammalian skeletal muscle differentiation. In addition, the results suggest a possible role of mechanosensitive Piezo1 channels in the modulation of TMEM16A currents.

Steel slag is a co-product of the steelmaking industry, this material is rarely used as a binder due to its low cementitious properties. Thus, it´s believed that the alkaline activation of steel slag can enable its use as a cementitious material. This work has the objective of making a systematic bibliographic review on the theme "slag melt as a precursor in activated alkali binders". To this end, the ProKnow-C method was used for the selection and analysis of relevant research on the topic. The portfolio resulted in 71 texts, mostly journals paper. Bibliometrics showed that the country with the most publications is China and the journal with the most publications is Construction and Building Materials. The critical analysis concluded that the XRD, XRF, and compressive strength tests are the most used for the characterization of the material. It is possible to establish that there are some knowledge gaps on the subject, such as better mechanical characterization and greater production of works with dosing by the one-part method.

Titanium dioxide nanoparticles (TiO2NPs) are used in products that are applied to the human body, such as cosmetics and food, but their biocompatibility remains controversial. Pycnogenol (PYC), a natural extract of pine bark, exerts anti-inflammatory and antioxidant effects. In this study, we investigated whether PYC effectively alleviates pulmonary toxicity induced by airway exposure to TiO2NPs, and the beneficial effects of PYC were explained through the analysis of changes to the mechanism of cytotoxicity. TiO2NPs induced pulmonary inflammation and mucus production, increased the levels of malondialdehyde, and upregulated thioredoxin-interacting protein (TXNIP) and cleaved-caspase 3 (Cas3) in the lungs of mice. However, PYC treatment reduced the levels of all toxicity markers of TiO2NPs and restored glutathione levels. These antioxidant and anti-inflammatory effects of PYC were also demonstrated in TiO2NP-exposed human airway epithelial cells by increasing the mRNA levels of antioxidant enzymes and decreasing the expression of TXNIP, cleaved-Cas3, and inflammatory mediators. Taken together, our results showed that PYC attenuated TiO2NP-induced lung injury via TXNIP downregulation. Therefore, our results suggest the potential of PYC as an effective anti-inflammatory and antioxidant agent against TiO2NP-induced pulmonary toxicity.

This review was carried out to identify different beta-lactamase resistance genes reported in published literature from Nigeria and to determine the proportion estimates of the important beta-lactamase resistance genes in Nigeria. Sixty-three (63) articles were included in this review based on the eligibility criteria. All the beta-lactamases reported were detected from the Gram-negative bacteria, most especially from Enterobacteriaceae (n=53). Thirty-six different beta-lactamase genes have been reported from Nigeria. These genes belong to the narrow-spectrum, AmpC, extended-spectrum, and carbapenemase beta-lactamase resistance genes. Eight (8) genes (bla_DHA, bla_CTXM-1, bla_CTXM-14, bla_GES-1, bla_VEB-1, bla_OXA-1, bla_OXA-2, and bla_TEM-1) were shared between animals and humans, 5 genes (bla_SHV-1, bla_SHV-2, bla_SHV-11, bla_SHV-12, and bla_NDM-1) were common to both humans and environment while none of the genes was unique to both animals and environment. Four genes including bla_CMY, bla_TEM-1, bla_AmpC, and internationally pandemic bla_CTXM-15 gene were unique to animals, humans, and the environment. No carbapenemase gene was reported from animals yet. The pooled proportion estimate of ESBL genes in Nigeria was 31% (95% CI: 26-36%, P<0.0001), while the estimate of bla_CTXM-15 gene in Nigeria was 46% (95% CI: 36-57%, P<0.0001). The proportion estimate of AmpC genes was 32% (95% CI: 11-52%, P<0.001), while the estimate for carbapenemases was 8% (95% CI: 5-12%, P<0.001). This study has provided information on the beta-lactamases distribution in Nigeria. This is necessary for a better understanding of molecular epidemiology of clinically important beta-lactamases especially the extended-spectrum beta-lactamases and carbapenemases in Nigeria.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiate an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of alternation in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method in the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in near future.

Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.

The SiBOC precursor ceramics were fabricated by polymer-derived method SiBOC precursors with different B/Si molar ratios were synthesized by controlling monomer content. The effects of different process conditions on SiBOC ceramics and the oxidation resistance of SiBOC ceramics at a high temperature (1400 ℃) were studied. The SiBOC precursor’s bonds of Si-O-C, Si-O-Si, and Si-O-B were detected by FTIR. The precursor is converted to a rigid ceramic material that has an 85.3 wt % ceramic yield of SiBOC ceramics with B/Si=0.4 by TG-DSC. The results of SEM analysis show that the SiBOC ceramics surface bulges and folds increase with the increase of boric acid content. With the increase of pyrolysis temperature and pyrolysis time, the size and number of pores on the surface of SiBOC ceramics also increase. Static oxidation tests show that SiBOC ceramics with B/Si=0.4 have better oxidation resistance under other conditions being the same.

Chlamydia trachomatis (Ct) infections are the most common sexually-transmitted infection (STI). Despite effective antibiotics for Ct, undetected infections or delayed treatment can lead to infertility, ectopic pregnancies, and chronic pelvic pain. Besides humans, chlamydia poses similar health challenges in animals such as C. suis (Cs) in pigs. Based on the similarities between humans and pigs as well as their chlamydia species, we use pigs as a large biomedical animal model for chlamydia research. In this study, we use the pig model to develop a vaccine candidate against Ct. The vaccine candidate consists of TriAdj-adjuvanted chlamydial protease-like activity factor (CPAF) protein. We tested two weekly administration options – twice intranasal (IN) followed by twice intramuscular (IM), or twice IM followed by twice IN. We assessed the humoral immune response not only in serum by CPAF-specific IgG including antibody avidity determination but also in cervical and rectal swabs by CPAF-specific IgG and IgA ELISAs. The systemic T-cell response was analyzed upon in vitro CPAF-restimulation via IFN-γ and IL-17 ELISpots as well as intracellular cytokine staining flow cytometry. Our data demonstrate that while the IN/IM vaccination mainly led to non-significant systemic immune responses, the vaccine candidate is highly immunogenic if administered IM/IN. This vaccination strategy induced high serum anti-CPAF IgG levels with strong avidity as well as high IgA and IgG levels in vaginal and rectal swabs and in uterine horn flushes. In addition, this vaccination strategy prompted a pronounced cellular immune response: Besides inducing IL-17 production, the vaccine candidate induced a strong IFN-γ response by CD4 T cells. In the IM/IN vaccinated pigs, these cells also significantly downregulated their CCR7 expression – a sign for differentiation into peripheral tissue homing effector/ memory cells. Conclusively, this study demonstrates strong immunogenicity of the IM/IN administered TriAdj-adjuvanted Ct CPAF vaccine candidate. Future studies will test vaccine efficacy of this promising Ct vaccine candidate. In addition, this project demonstrates suitability of the Cs pre-exposed outbred pig model for Ct vaccine development. Thereby, we aim to open the bottleneck of large animal models to facilitate the progression of Ct vaccine candidates into clinical trials.

Studies on crop response to light quality [red (R) to far-red (FR) light ratio] often recommend early weed removal to reduce the effects of shade avoidance responses on crop yield. However, it is unclear whether crops are able to distinguish reflected light quality of kin from that of non-kin. We evaluated the response of sugarbeet (Beta vulgaris L.) to reflected FR light from sugarbeet, common lambsquarters (Chenopodium album L.), Kentucky bluegrass (Poa pratensis L.), alfalfa (Medicago sativa L.), and bare soil (control) under outdoor conditions in 2016 and 2017. Treatments were completely randomized with 10 replications per treatment. The study methods ensured there was no direct resource competition. The reflected R:FR of plant species ranged from 0.06 (common lambsquarters) to 0.24 (sugarbeet) compared to 0.7 for the bare soil. In both 2016 and 2017, there were 2 to 4 more leaves in the sugarbeet surrounded by soil compared to sugarbeet surrounded by neighboring species. There was up to 47, 57, 43, and 23% reduction in sugarbeet leaf area, shoot dry weight, root diameter, and root dry weight, respectively, due to reflected R:FR light from neighboring species. Sugarbeet did not respond differently to reflected light quality of kin compared to non-kin.

The photosystem I (PSI) of the green alga Chlamydomonas reinhardtii associates with 10 light-harvesting proteins (LHCI) to form the PSI-LHCI complex. Binding of LHCII to PSI may also occur and is controlled by a process called state transitions. Hereby, two LHCII trimers bind to the PSAL, PSAH and PSAO side of PSI to produce the PSI-LHCI-LHCII complex. In this work, we took advantage of chemical crosslinking of proteins in conjunction with mass spectrometry to identify protein-protein interactions between the light-harvesting proteins of PSI and PSII. We detected binding of LHCBM proteins to the LHCA1-PSAG side of PSI and identified protein-protein interactions of LHCSR3 with LHCA5 and LHCA3. Our data indicate that the binding of LHCII to PSI is more versatile as anticipated and reveal that LHCSR3 likely regulates excitation energy transfer to the PSI core via LHCA5/LHCA3.

Infective endocarditis is a rare and challenging diagnosis, Q fever endocarditis being a major cause of culture-negative endocarditis (IE). The presence of multiple cerebral microbleeds (CMBs) suggests a particular vascular frailty and could be correlated to potential emergence of a haemorrhagic stroke in IE. We report a case of a 45 years-old patient with Coxiella burnetii endocarditis, with a brainstem hemorrhage and cerebral MRI CMBs resembling those of CAA. However the systemic inflammatory tests, the splenic infarct and kidney pathology could not be explained by a variant of CAA, neither the normal initial cerebral CT scan when the patient had already the brainstem clinical signs without evidencing the hemorrhage. Transthoracic and transesophageal echocardiogram revealed only calcified bicuspid aortic valve with moderate stenosis and regurgitation, without any vegetations and the blood cultures on conventional media were negative. Serology for Coxiella burnetii was positive. Inclusion of CMBs as a new minor imaging criteria for infective endocarditis could upgrade the diagnosis in almost 50% of patients.

The application of Explainable AI (XAI) to improve understanding of complex non-linear SST teleconnections and gain predictive skills is at the frontier of climate research. In this study, we attempt to refine the applications of XAI advancements to ENSO prediction by including SSTA in the western North Pacific (WNP) as a precursor. Our analyses indicate that the baseline accuracy increases from the 60% threshold previously reported for ENSO to &gt;85% for moderate warm, cold, and neutral ENSO states one year in advance when WNP SSTA is included. Precision increases to over 90% for higher magnitude El Niños and La Niñas. Experiments conducted at 4-year lead times yield a strong WNP SSTA signal. A moderate SSTA signal is observed at 3-year lead time with no predictability; however, predictability spikes to over 80% when stratospheric zonal winds are included with WNP SSTA. While additional scientific work is required to make robust connections between XAI and dynamical processes, our results demonstrate a potential to improve long term predictability of ENSO through the ability of XAI in capturing SST patterns evolving at extended spatial and temporal scales.

Owing to their extraordinary properties, carbon-based nanomaterials are gaining traction in biomedicine. Green synthesis is the cost-effective method for fabricating carbon-based nanomaterials due to its rapidity, renewable nature, and sustainability. This study emphasis on the graphene oxide (GO) reduction using a simple one-pot technique that does not require the use of toxic reducing agents. This article reports the green synthesis of reduced graphene oxide (RGO) using Hibiscus sabdariffa L. calyxes extract as the natural reducing agent. Additionally, this article also provides analysis RGO using X-ray diffraction (XRD), UV-Visible spectroscopy (UV-Vis), and Raman spectroscopy. XRD result showed that the GO peak at 11o diminished, and a new hump appear at 22o indicating that the GO is fully reduced when it is refluxed for 6 hours, at 100oC with 1:3 ratio of GO:PE. The UV-Vis data indicated absorption peak of GO (237 nm) and RGO (265 nm) at distinct locations. This finding shed new light on the enormous potential of Hibiscus sabdariffa L. calyxes extract for green GO reduction. As a result, this environmentally friendly method can help reduce dependence on chemical materials.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Virus taxonomy uses a Linnaean-like subsumption hierarchy to classify viruses into taxonomic units at species and higher rank levels. Virus species are considered monophyletic groups of mobile genetic elements (MGEs) often delimited by phylogenetic analysis of aligned genomic or metagenomic sequences. Taxonomic units are assumed independent organizational, functional and evolutionary units that follow a ‘natural’ historical rationale. Here, I use phylogenomic and other arguments to show that viruses are not self-standing genetically-driven biological systems. Instead, they are crucial components of holobionts, units of biological organization that dynamically integrate the genetics, epigenetic, physiological and functional properties of their co-evolving members. Remarkably, phylogenomic analyses show viruses share protein domain and loop structures with cells throughout history via massive processes of reticulate evolution, helping spread evolutionary innovations across a wider taxonomic spectrum. Thus, viruses are not merely MGEs or microbes. Instead, their genomes and proteomes conduct cellularly integrated processes akin to those cataloged by the GO Consortium. This prompts the generation of compositional hierarchies that replace the ‘is-a-kind-of’ by a ‘is-a-part-of’ logic to better describe the mereology of integrated cellular and viral makeup. My analysis demands a new paradigm that integrates virus taxonomy into a modern evolutionarily centered taxonomy of organisms.