We designed a novel growth controller regulated by feeding of an unnatural amino acid, Nε-benzyloxycarbonyl-L-lysine (ZK), using a specific incorporation system at a sense codon. This system is constructed by a pair of modified pyrrolisyl-tRNA synthetase (PylRS) and its cognate tRNA (tRNApyl). Although ZK is non-toxic for normal organisms, the growth of Escherichia coli carrying the ZK incorporation system was inhibited in a ZK concentration-dependent manner without causing rapid bacterial death, presumably due to generation of non-functional or toxic proteins. The extent of growth inhibition strongly depended on the anticodon sequence of the tRNApyl gene. Taking advantage of the low selectivity of PylRS for tRNApyl anticodons, we experimentally determined the most effective anticodon sequence among all 64 nucleotide sequences in the anticodon region of tRNApyl gene. The results suggest that the ZK-regulated growth controller is a simple, target-specific, environmental noise-resistant and titratable system. This technique may be applicable to a wide variety of organisms because the growth inhibitory effects are caused by “informational disturbance”, in which the highly conserved system for transmission of information from DNA to proteins is perturbed.

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by the impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degree of mental retardation, autism, ataxia and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential use of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between the researchers and the patients.

We construct a novel family of summation-integral type hybrid operators in terms of shape parameter $\alpha\in \lbrack 0,1]$ in this paper. Basic estimates, rate of convergence, and order of approximation are also studied using the Korovkin theorem and the modulus of smoothness. We investigate the local approximation findings for these sequences of positive linear operators utilising Peetre's K-functional, Lipschitz class, and second-order modulus of smoothness.

This study assessed bio-equivalence of high-quality, plant-based protein blends versus Whey Protein Isolate (WPI) in healthy, resistance-trained men. The primary endpoint was incremental area under the curve (iAUC) of blood essential Amino Acids (eAAs) 4 hours after consumption of each product. Cmax and Tmax of blood leucine were secondary outcomes. Subjects (n=18) consumed three plant-based protein blends and WPI (control). Analysis of Variance model was used to assess for bio-equivalence of total sum of blood eAA concentrations. The total blood eAA iAUC ratios of the three blends were: [90% CI]: #1: 0.66 [0.58-0.76]; #2: 0.71 [0.62-0.82]; #3: 0.60 [0.52-0.69], not completely within the pre-defined equivalence range [0.80-1.25], indicative of 30-40% lower iAUC versus WPI. Leucine Cmax of the three blends was not equivalent to WPI, #1: 0.70 [0.67-0.73]; #2: 0.72 [0.68-0.75]; #3: 0.65 [0.62 – 0.68], indicative of a 28-35% lower response. Leucine Tmax for two blends were similar to WPI (#1: 0.94 [0.73-1.18]; #2: 1.56 [1.28-1.92]; #3: 1.19 [0.95-1.48]). The plant-based protein blends were not bio-equivalent. However, blood leucine kinetic data across the blends approximately doubled from fasting concentrations whereas blood Tmax data across two blends was similar to WPI. This suggests evidence of rapid hyperleucinemia, which correlates with a protein’s anabolic potential.

Cystathionine gamma-lyase (CSE) is an essential Hydrogen sulphide (H2S)-producing enzyme that regulates diverse processes related to cardiovascular function. It is crucial to understand how exogenous H2S regulates CSE expression in vascular endothelial cells during hypoxia. We examined the regulatory effect of 100 μM H2S on the transcription and expression of CSE in HUVECs during hypoxia by luciferase assay, Western blotting, and quantitative RT-qPCR. Exogenous H2S influenced the promoter activity of CSE in HUVECs during hypoxia. Compared with 0 μM H2S, 100 μM H2S decreased the mRNA expression of CSE in HUVECs. Compared with 0 μM H2S, 100 μM H2S decreased the protein expression of CSE in HUVECs after 2 h of hypoxia. These findings suggest that vascular endothelial cells can respond to changes in H2S concentration in the blood during hypoxia.

We investigate new graph characteristics namely total (vertex, edge) face irregularity strength of gen- eralized plane grid graphs Gmn under k-labeling Phi of type (Alpha, Beta, Gamma). The minimum integer k for which a vertex-edge labelled graph has distinct face weights is called the total face irregularity strength of the graph and is denoted by tfs(Gmn). In this article, the graphs G = (V;E; F) under consideration are simple, finite, undirected and planar. We will estimate the exact tight lower bounds for the total face irregularity strength of some families of generalized plane grid graphs.

Pairs of pyrrolysyl-tRNA synthetase (PylRS) and tRNAPyl from Methanosarcina mazei and Methanosarcina barkeri are widely used for site-specific incorporations of non-canonical amino acids into proteins (genetic code expansion). Previously, we achieved full productivity of cell-free protein synthesis for bulky non-canonical amino acids, including Ne-((((E)-cyclooct-2-en-1-yl)oxy)carbonyl)-L-lysine (TCO*Lys), by using Methanomethylophilus alvus PylRS with structure-based mutations in and around the amino acid binding pocket (first-layer and second-layer mutations, respectively). Recently, the PylRS•tRNAPyl pair from a methanogenic archaeon ISO4-G1 was used for genetic code expansion. In the present study, we determined the crystal structure of the methanogenic archaeon ISO4-G1 PylRS (ISO4-G1 PylRS) and compared it with those of structure-known PylRSs. Based on the ISO4-G1 PylRS structure, we attempted the site-specific incorporation of Ne-(p-ethynylbenzyloxycarbonyl)-L-lysine (pEtZLys) into proteins, but it was much less efficient than that of TCO*Lys with M. alvus PylRS mutants. Thus, the first-layer mutations (Y125A and M128L) of ISO4-G1 PylRS, with no additional second-layer mutations, increased the protein productivity with pEtZLys up to 578% of that with TCO*Lys, at high enzyme concentrations in the cell-free protein synthesis.

Nonporous corundum powder, known as an abrasive material in the industry, was functionalized covalently with protein binders to isolate and enrich specific proteins from complex matrices. The materials based on corundum were characterized by TEM, ESEM, BET, DLS, and zeta potential measurements. The strong Al-O-P bonds between the corundum surface and amino phosphonic acids are used to introduce functional groups for further conjugations. The common crosslinker glutaraldehyde was compared with a hyperbranched polyglycerol (PG) of around 10 kDa. The latter is oxidized with periodate to generate aldehyde groups that can covalently react with the amines of the surface and the amino groups from the protein via a reductive amination process. The amount of bound protein was quantified via aromatic amino acid analysis (AAAA). This work shows that oxidized polyglycerol can be used as an alternative to glutaraldehyde. With polyglycerol, more of the model protein bovine serum albumin (BSA) could be attached to the surface under the same conditions, and lower nonspecific binding (NSB) was observed. As a proof of concept, IgG was extracted with protein A from crude human plasma. The purity of the product was examined by SDS-PAGE. A binding capacity of 1.8 mg IgG per g of corundum powder was achieved. The advantages of corundum are the very low price, extremely high physical and chemical stability, pressure resistance, favorable binding kinetics, and flexible application.

The development of Imaging Atmospheric Cherenkov Telescopes (IACTs) unveiled the sky in the teraelectronvolt regime, initiating the so-called “TeV revolution” at the beginning of the new millennium. This revolution was also facilitated by the implementation and adaptation of statistical tools for analyzing the shower images collected by these telescopes and inferring the properties of the astrophysical sources that produce such events. The image reconstruction techniques, the background discrimination and the signal-detection analyses are just a few of the pioneering studies applied in the last decades in the analysis of IACTs data. This (succinct) review has the intent of summarizing the most common statistical tools that are used for analyzing data collected with IACTs, focusing on their application in the full analysis chain, giving references to the past literature for a deepened examination.

Potato is among one of the most important food crops, yet maintaining plant productivity in this drought-sensitive crop has become a challenge. Competition for scarce water resources and the continued effects of global warming exacerbate current constraints on crop production. While plants’ response to drought in above-ground tissues has been well documented, the regulatory cascades in developing tubers have been largely unexplored. Using the commercial Canadian cultivar ‘Vigor’, plants were subjected to a drought treatment under high-tunnels causing a 4 ℃ increase in canopy temperature when compared to the well-watered control. Tubers were sampled for RNAseq and metabolite analysis. Approximately 2600 genes and 3898 transcripts were differentially expressed by at least four-fold in drought-stressed potato tubers, with 75 % and 69 % being down-regulated respectively. A further 229 small RNAs were implicated in gene regulation during drought. The comparison of protein homologues between Solanum tuberosum L. and Arabidopsis thaliana L. indicates that downregulated genes are associated with phenylpropanoid, carotenoid, and patatin biosynthesis. This suggests that there may be nutritive implications to drought stress occurring during the potato tuber bulking phase in sensitive cultivars.

A critical analysis of the classical definition of outsiders is given. Some examples show that this notion is not universal and has at least two drawbacks. Particularly, the set of outsiders may have the probability arbitrary close to one half. On the other hand, the deleting of the set of outsiders may dramatically change the value of the median.

The manuscript surveys the special functions of the Fox-Wright type. These functions are generalizations of the hypergeometric functions. Notable representatives of the type are the Mittag-Leffler functions and the Wright function. The integral representations of such functions are given and the conditions under which these function can be represented by simpler functions are demonstrated. The connection with generalized fractional differential and integral operators is demonstrated and discussed.

Saif et al. (J. Math. Comput. Sci. 21 (2020) 127-135) considered modified Laplace transform and developed some of their certain properties and relations. Motivated by this work, in this paper, we define modified Sumudu transform and investigate many properties and relations including modified Sumudu transforms of the power function, sine, cosine, hyperbolic sine, hyperbolic cosine, exponential function, and function derivatives. Moreover, we attain two shifting properties and a scale preserving theorem for the modified Sumudu transform. We give modified inverse Sumudu transform and investigate some relations and examples. Furthermore, we show that the modified Sumudu transform is the theoretical dual transform to the modified Laplace transform.

In this paper we introduce the New/Generalized two parameter Gamma function and Pochhammer symbol. We named them, as Generalized p - k Gamma Function and Generalized p - k Pochhammer symbol and denoted as $ _{p}^{a}\Gamma_{k}(x) $ and $ _{p}^{a}(x)_{n,k} $ respectively. We prove the several identities for $ _{p}^{a}\Gamma_{k}(x) $ and $ _{p}^{a}(x)_{n,k} $ those satisfied by the classical Gamma function. Also we provide the integral representation for the $ _{p}^{a}\Gamma_{k}(x) $

In this note we construct explicit complex and real matrix representations for the generators of real Clifford algebra $C\ell_{p,q}$. The representation is based on Pauli matrices and has an elegant structure similar to the fractal geometry. We find two classes of representation, the normal representation and exceptional one. The normal representation is a large class of representation which can only be expanded into $4m+1$ dimension, but the exceptional representation can be expanded as generators of the next period. In the cases $p+q=4m$, the representation is unique in equivalent sense. These results are helpful for both theoretical analysis and practical calculation. The generators of Clifford algebra are the faithful basis of $p+q$ dimensional Minkowski space-time or Riemann space, and Clifford algebra converts the complicated relations in geometry into simple and concise algebraic operations, so the Riemann geometry expressed in Clifford algebra will be much simple and clear.

Here, I present an alternate solution for the dark matter problem. I show that the stars of a galaxy’s arm attract each other with a force other than gravity, producing a chain of stars. We already have an abundance of data (ring and multiring galaxies) as proof for the existence of this strong stars’ chain. This attraction force does not end at the galaxy’s boundaries but gets deeper into the cosmos, and it may explain the dark-energy problem. This attraction force affects only stars and seems to have no effect on planets. I also offer a novel timeline order for the well-known galaxies using Hubble classification. I nominate entangled particles for the role that causes this phenomenon.

Background: The present retrospective study was designed to evaluate the relative diagnostic utility of breast-specific gamma imaging (BSGI) and breast magnetic resonance imaging (MRI) as means of evaluating female breast cancer patients in China. Methods: A total of 229 malignant breast cancer patients underwent ultrasound, mammography, BSGI, and MRI between January 2015 and December 2018 for initial tumor staging. Of these patients, 73 were subsequently treated via definitive breast surgery following neoadjuvant chemotherapy (NAC), of whom 17 exhibited a complete pathologic response (pCR) to NAC. Results: BSGI and MRI were associated with respective 76.8% and 69.6% sensitivity values as a means of detecting residual tumors following NAC, while both of these approaches exhibited comparable specificity in this diagnostic context (58.8% vs 70.6%, P=0.473). Conclusion: These results demonstrate that BSGI is a useful auxiliary approach to evaluating pCR to NAC treatment.

Theories of quantum gravity suggest that Lorentz invariance, the fundamental symmetry of the Theory of Relativity, may be broken at the Planck energy scale. While any deviation from conventional Physics must be minuscule in particular at attainable energies, this hypothesis motivates ever more sensitive tests of Lorentz symmetry. In the photon sector, astrophysical observations, in particular polarization measurements, are a very powerful tool because tiny deviations from Lorentz invariance will accumulate as photons propagate over cosmological distances. The Standard-Model Extension (SME) provides a theoretical framework in the form of an effective field theory that describes low-energy effects due to a more fundamental quantum gravity theory by adding additional terms to the Standard Model Lagrangian. These terms can be ordered by the mass dimension d of the corresponding operator and lead to a wavelength, polarization, and direction dependent phase velocity of light. In this paper, we analyze optical polarization measurements from 63 Active Galactic Nuclei (AGN) and Gamma-ray Bursts (GRBs) in order to search for Lorentz violating signals. We derive the first set limits on each of the 10 individual birefringent coefficients of the minimal SME with d = 4, with 95% confidence limits on the order of 10⁻³⁴ on the dimensionless coefficients.

Introduction: Tuberculosis (TB) is one of the most prevalent respiratory diseases in the world. In 2020 there were at least 9.9 million new infections, with 1.5 million deaths. Approximately 10% of people infected with Mycobacterium tuberculosis (LTBI) develop the disease during the first 2 to 5 years after infection. Currently in South America, the diagnosis of LTBI continues to be per-formed through the Mantoux tuberculin skin test (TST). Objective: The objective of our study was to compare the sensitivity of a new immunofluorescence IGRA test against a widely available IGRA kit on the market. Material and method: Close contact to infectious patients with TB, or HIV patients or immunocompromised for another cause were recruited. Two interferon gamma release assay (IGRA) diagnostic kits were used and compared with TST. Results: 76 patients were recruited. 93.42% were Chilean nationality, 98.68% of the patients did not have immunosuppres-sion. The sensitivity of the new technique was 88.89% and specificity 92.50% in the study popula-tion compared to the IGRA previously used. In the subgroup older than 36 years, the sensitivity was 95.65% and the specificity 89.47%. Conclusion: IGRA techniques are a new resource in clini-cal laboratories to be able to make an accurate diagnosis in LTBI in the region of the Americas. In our population, the greatest benefit of this new IGRA would be observed in people over 36 years of age, where the sensitivity of the technique was like that of the currently available test.

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin releasing factor (CRF)-CRF1 receptor and GABAergic signaling dysregulation occurring in alcohol dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch clamp electrophysiology to examine the effects of alcohol dependence on the CRF-modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had less CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.

With the extension of the post-catch circulation time, a series of changes had taken place in the soft tissue of the live clams, resulting in the decline of its quality. This study investigated the quality changes of clams (Ruditapes philippinarum) in cold chain and was mainly focused on the rehydration process, which included gradient heating rehydration (GR) and sudden heating rehydration (SR). It was found that the GR had a better effect on the quality of clams than the SR. The GR stage clams showed a higher survival rate, glycogen content and adenylate energy charge (A.E.C) value than the SR stage clams. Conversely, the GR stage clams showed lower lactic acid content and K-value than the SR stage clams. The results indicated that the gradient heating rehydration was beneficial to the quality of clams. The transportation and rehydration strategies benefited both producers and shellfish merchants to save total cost.

The article describes synthesis of aminoorgano-functionalized silica as a perspective material for catalysis application. The amino groups have electron donor properties valuable for metal chemical state of palladium. So presence of electron donor groups is important for increasing of catalysts stability. The research is devoted to investigation of silica amino-modified support influence on activity and stability of palladium species in 4-nitroaniline hydrogenation process. A series of catalysts with different supports such as SiO2, SiO2-C3H6-NH2 (amino-functionalized silica), γ-Al2O3 and activated carbon were studied. The catalytic activity was studied in the hydrogenation of 4-nitroaniline to 1,4-phenylenediamine. The catalysts were characterized by scanning electron microscopy, transmission electron microscopy, x-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and pulse chemisorption of hydrogen. The 5 wt. % Pd/SiO2-C3H6-NH2 catalyst exhibited the highest catalytic activity for 4-nitroaniline hydrogenation with 100% conversion and 99% selectivity with respect to 1,4-phenylenediamine.

In this study, we once again use a set of Fibonacci-like sequences to examine the symmetries within the genetic code. This time, our focus is on the physiological state of the amino acids, considering them as charged, in contrast to our previous work where they were seen as neutral. In a pH environment around 7.4, there are four charged amino acids. We utilize the properties of our sequences to accurately describe the symmetries in the genetic code table. These include Rumer’s symmetry, the third-base symmetry and the "ideal" symmetry, along with the "supersymmetry" classification schemes. We also explore the special chemical structure of the amino acid proline, presenting two perspectives—shCherbak’s view and the Downes-Richardson view, which perspectives are included in the description of the above-mentioned symmetries. Our investigation employs also elementary modular arithmetic to precisely describe the chemical structure of proline, connecting the two views seamlessly. Finally, our Fibonacci-like sequences prove instrumental in quickly establishing the multiplet structure of non-standard versions of the genetic code. We illustrate this with an example, showcasing the efficiency of our method in unraveling the complex relationships within the genetic code.

This research evaluates the inhibitory effect of L-amino acids (AAs) with different side chain lengths on Fe surface implementing Monte Carlo (MC) simulation. A quantitative and qualitative description of the adsorption behavior of AAs on the iron surface has been carried out. Calculations have shown that the absolute values of the adsorption energy of L-amino acids increase with side chain prolongation; they are also determined by the presence of heteroatoms. AAs from nonpolar and basic groups have the best adsorption ability to the iron surface, which indicates their highest inhibitory efficiency according to the results of MC simulation.

In this study dual PET and contrast enhanced MRI were combined to investigate their correlation per voxel in patients at initial diagnosis with suspected glioblastoma. Correlation with contrast enhancement (CE) as an indicator of BBB leakage was further used to evaluate whether PET signal is likely caused by BBB disruption alone, or rather attributable to specific binding after BBB passage. PET images with [18F]GE180 and the amino acid [18F]FET were acquired and normalized to healthy background (TBR). Contrast enhanced images were normalized voxel by voxel with the pre-contrast T1-weighted MRI to generate relative CE values (rCE). Voxel-wise analysis revealed a high PET signal even within the sub-volumes without detectable CE. No to moderate correlation of rCE with TBR voxel-values and a small overlap as well as a larger distance of the hotspots delineated in rCE and TBR-PET images were detected. In contrast, voxel-wise correlation between both PET modalities was strong for most patients and hotspots showed a moderate overlap and distance. The high PET signal in tumor sub-volumes without CE observed in voxel-wise analysis as well as the discordant hotspots emphasize the specificity of the PET signals and the relevance of combined differential information from dual PET and MRI images.

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were used as positive controls. AA manipulation led to modest improvements in mice survival when the levels or lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Mice fed the artificial diets as monotherapy lived longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (ΔG_bind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.

Gamma titanium aluminides (γ-TiAl) present an excellent behaviour under high temperature conditions, being a feasible alternative to nickel-based superalloy components in aeroengine sector. However, considered as a difficult to cut material, process cutting parameters require special study to guarantee components quality. In this work, developed drilling mechanistic model is a useful tool in order to predict drilling force (F_z) and torque (T_c) for optimal drilling conditions determination. The model is validated for three types of Gamma-TiAl alloys. Integral hard metal end-drilling tools and different cutting parameters (feeds and cutting speeds) are tested in three different sized holes for each alloy.

In this paper we re-investigated the relationship between the symmetry of inertial systems and the Lorentz transformation. We found that when we just follow the following three principles: (1)we can define the time in the whole space with a prescribed clock synchronization, (2)the time-space is uniform and the space is isotropic and (3)all the inertial systems are equivalent, then we can totally construct a general coordinate transformation to meet the symmetry of inertial systems, and with a special assumption on the speed of light, we can construct a non-Lorentz transformation between inertial systems to make the particle’s energy have a limited value, which is similar to the rainbow model. Similar to the usual Lorentz violating models, the non-Lorentz transformation in this paper lead to a new modified disperse relation. We applied the obtained disperse relation to analyze the photon’s arrival time lag effect in astronomy and found that the "maximum energy" derived in our model is somewhat related to the "maximum energy" assumed in the rainbow model.

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided in three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, and terrestrial ecosystems. The health significance of these metabolites, which include genotoxic- and neurotoxic agents, is confirmed by continued associations between the occurrence of animal and human acute toxic events and, in the long term, by associations between cyanobacteria and neurodegenerative diseases. One of the implicated mechanisms includes a misincorporation of cyanobacterial non-proteogenic amino acids leading to mistranslation and protein misfolding. A better understanding of the interaction between the cyanopeptide metabolism and the nervous system will be crucial to target or to prevent pathogenic response.

We research the interaction between six representative carbon-based nanoparticles (CBNs) and 20 standard amino acids through all-atom molecular dynamics simulations. The six carbon-based nanoparticles are fullerene(C60), CNT55L3, CNT1010L3, CNT1515L3, CNT2020L3, and two-dimensional-graphene(Graphene33). Their curvatures decrease sequentially, and all of CNT are single-walled carbon nanotubes. We have observed that as the curvature of CBNs decreases, the adsorption effect of 20 amino acids with them has an increasing trend. In addition, we also used multi-dimensional clustering to analyze the adsorption effects of 20 amino acids on six carbon-based nanoparticles. We observed that the π-π interaction still plays an extremely important role in the adsorption of amino acids on carbon-based nanoparticles. Individual long-chain amino acids and “Benzene-like” Pro also have a strong adsorption effect with carbon-based nanoparticles.

Understanding the spatially varying effects of demographic factors on the spatio-temporal variation of intestinal parasites infections is important for public health intervention and monitoring. This paper presents a hierarchical Bayesian spatially varying coefficient model to evaluate the effects demographic factors on intestinal parasites morbidities in Ghana. The modeling relied on morbidity data collected by the District Health Information Management Systems. We developed Poisson and Poisson-gamma spatially varying coefficient Models. We used the demographic factors, unsafe drinking water, unsafe toilet and unsafe liquid waste disposal as model covariates. The models were fitted using the Integrated Nested Laplace Approximations (INLA). The overall risk of intestinal parasites infection was estimated to be 10.9 per 100 people with a wide spatial variation in the district-specific posterior risk estimates. Substantial spatial variation of increasing multiplicative effects of unsafe drinking water, unsafe toilet and unsafe liquid waste disposal occurs on the variation of intestinal parasites risk. The structured residual spatial variation widely dominates the unstructured component, suggesting that the unaccounted-for risk factors are spatially continuous in nature. The study concludes that both the spatial distribution of the posterior risk and the associated exceedance probability maps are essential for monitoring and control of intestinal parasites.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 – 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

Roses are one of the most important floricultural crops, and their essential oils have long been used for cosmetics and aromatherapy. We investigated the volatile compound compositions of 12 flower-color mutant variants and their original cultivars. Twelve rose mutant genotypes were developed by treatment with 70 Gy of 60Co gamma irradiation of six commercial rose cultivars. Essential oils from the flowers of the 18 genotypes were analyzed by gas chromatography–mass spectrometry. Seventy-seven volatile compounds were detected, which were categorized into five classes: hydrocarbons, terpenoids, alcohols, esters, and others. Hydrocarbons, alcohols, and esters were major components in all rose flowers. The mutant genotypes CR-S8 and CR-S9 showed higher contents of hydrocarbons than the original cultivar. In addition, CR-S1, CR-S3, and CR-S4 mutant genotypes showed higher ester contents than their original cultivar. Nonacosane, 2-methylhexacosane, and 2-methyltricosane were major volatile compounds among all genotypes. Hierarchical cluster analysis of the rose genotypes gave four groups according to grouping among the 77 volatile compounds. These findings will be useful for the selection of rose genotypes with improved volatile compounds.

Genetic code expansion has emerged as an enabling tool to provide insight into functions of understudied proteinogenic species such as small proteins and peptides, and to probe protein biophysics in the cellular context. Here we discuss recent technical advances and applications of genetic code expansion in cellular imaging of complex mammalian protein species, along with considerations and challenges upon using the method.

In this review, we present the latest exclusion limits obtained with astroparticles for Lorentz Invariance Violation (LIV) in the photon sector. We discuss the techniques known as energy-dependent time delay or time lag, subluminal pair production threshold shift, superluminal photon decays and superluminal photon splitting. Perspectives for future results in LIV with the next generation of experiments are also addressed.

Hubble diagrams are examined for SN1a supernovae in the redshift range z = 0.01–1.3 and for gamma ray bursts in the range z = 0.034–8.1. It is shown that in the low redshift range, the Hubble diagram shows an innate equivocality between the ΛCDM and the tired light model. This means that the strong agreement between the z/µ data, calculated with the parameters of the ΛCDM model, and the experimentally measured z/µ values cannot be considered as definite evidence for the expansion hypothesis. The exponential function , which is characteristic of the tired light redshift mechanism, fits the data with similarly high accuracy. Hence, on the premise of low redshift data, a decision for or against either model is completely arbitrary. The Hubble diagram for high redshift gamma ray bursts shows poor agreement with the ΛCDM model, but concurs with the exponential energy decay following from the tired light redshift hypothesis.

In this paper, modelling designing and simulation of a Ward Leonard layout system is done using robust control theory. In order to increase the performance of the Ward Leonard layout system with H infinity optimal control synthesis and H infinity optimal control synthesis via gamma-iteration controllers are used. The open loop response of the Ward Leonard layout system shows that the system needs to be improved. Comparison of the Ward Leonard layout system with H∞ optimal control synthesis and H infinity optimal control synthesis via gamma-iteration controllers to track a desired step speed input have been done. Finally, the comparative simulation results prove the effectiveness of the proposed Ward Leonard layout system with H infinity optimal control synthesis controller in improving the percentage overshoot and the settling time.

Over the past decade, our knowledge of the $\gamma$-ray sky has been revolutionized by ground- and space-based observatories by detecting photons up to several hundreds of tera-electron volt (TeV) energies. A major population of the $\gamma$-ray bright objects are active galactic nuclei (AGN) with their relativistic jets pointed along our line-of-sight. Gamma-ray emission is also detected from nearby mis-aligned AGN such as radio galaxies. While the TeV-detected radio galaxies ($TeVRad$) only form a small fraction of the $\gamma$-ray detected AGN, their multi-wavelength study offers a unique opportunity to probe and pinpoint the high-energy emission processes and sites. Even in the absence of substantial Doppler beaming $TeVRad$ are extremely bright objects in the TeV sky (luminosities detected up to $10^{45}~erg~s^{-1}$), and exhibit flux variations on timescales shorter than the event-horizon scales (flux doubling timescale less than 5 minutes). Thanks to the recent advancement in the imaging capabilities of high-resolution radio interferometry (millimeter very long baseline interferometry, mm-VLBI), one can probe the scales down to less than 10 gravitational radii in $TeVRad$, making it possible not only to test jet launching models but also to pinpoint the high-energy emission sites and to unravel the emission mechanisms. This review provides an overview of the high-energy observations of $TeVRad$ with a focus on the emitting sites and radiation processes. Some recent approaches in simulations are also sketched. Observations by the near-future facilities like Cherenkov Telescope Array, short millimeter-VLBI, and high-energy polarimetry instruments will be crucial for discriminating the competing high-energy emission models.

Malaria rapid diagnosis test (RDT) is crucial for managing the disease, and the effectiveness of detection depends on parameters such as sensitivity and specificity of the RDT. Several factors can affect the performance of RDT. In this study, we focus on pfhrp2 sequence variation and its impact on RDTs targeted by antigens encoded by pfhrp2. Field samples collected during cross-sectional surveys in Tanzania were sequenced to investigate pfhrp2 sequence diversity and evaluate the impact on HRP2-based RDT performance. We observed significant mean differences in amino acid repeats between current and previous studies. Several new amino acid repeats were found to occur at different frequencies, including types AAY, AHHAHHAAN and AHHAA. Based on the abundance of types 2 and 7 amino acid repeats, the binary predictive model was able to predict RDT insensitivity by about 69 % in the study area. About 85% of the major epitopes targeted by Monoclonal antibodies (MAbs) in RDT were identified. Our study suggests that the extensive sequence variation in the pfhrp2 could contribute to reduced RDT sensitivity. The correlation between the different combinations of amino acid repeats and the performance of RDT in different malaria transmission settings should be investigated further.

Proof of the Riemann hypothesis is obtained using the properties of the Gamma function, the Bernoulli function, and limitations imposed by the rational relations of the complex roots of the Riemann zeta function, and the rational relations of the complex Gamma functions.

This article describes a novel topical composition constituted by gamma-amino butyric acid (GABA) and microbial chondroitin sulfate. This composition, formulated by the author and manufactured in a certified facility in the United States of America, exhibits potential for non-invasive intervention in anxiety management, sleep quality enhancement, and promotion of brain-related functions like meditation and nonlocal consciousness. The core component comprises GABA, a key inhibitory neurotransmitter within the central nervous system, complexed with a suitable carrier molecule, microbial chondroitin sulfate. This complexation aims to enhance transdermal absorption and optimize delivery of GABA to target tissues. The proposed mechanism of action involves modulation of GABAergic signal transduction pathways. Application of the topical composition allows GABA penetration into the skin and potentially deeper tissues, where it interacts with GABA receptors. This interaction leads to mental calmness and relaxation as assessed by electroencephalography. The influence of GABAergic signaling on brain circuits demonstrated in this article, when associated with meditation and nonlocal consciousness, suggests potential for the composition to support these practices. The advantage of such an approach consists in avoiding the potential systemic side effects associated with oral or injectable administration of GABA, anxiolytics or hypnotics. Furthermore, the combination of GABA and microbial chondroitin sulfate may offer synergistic benefits, potentially enhancing the overall biological effects. In conclusion, this article presents a novel topical approach for managing anxiety, enhancing sleep quality, and potentially facilitating meditation and nonlocal consciousness through modulation of GABAergic signaling pathways. While further research is necessary, the potential for a non-invasive and potentially side-effect-free intervention in these areas is promising.

Surface modification of polypropylene (PP) films is achieved using gamma-irradiation-induced grafting to proffer with antimicrobial activity. The copolymer was obtained through a versatile two-step route; pristine PP is exposed to gamma rays and grafted using methyl methacrylate (MMA), then N-vinylimidazole (NVI) is grafted onto the copolymer PP-g-MMA by simultaneous irradiation. The characterization included Fourier-Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscope (SEM), Thermogravimetric Analysis (TGA), X-ray Photoelectron Spectroscopy (XPS), and physicochemical analysis of swelling and contact angle. The copolymer (PP-g-MMA)-g-NVI was loaded with vancomycin, and the drug released was quantified by UV-vis spectrophotometry at different pH. The surface of (PP-g-MMA)-g-NVI exhibited pH-responsiveness and moderate hydrophilicity, suitable properties for controlled drug release.

We studied surface enhanced Raman spectra of amino acids D-alanine and DL-serine and their mixture on silver nanoisland films (SNF), immersed in phosphate buffer saline solution at millimolar amino acid concentrations. It is shown that the spectra from the amino acid solutions differ from the reference spectra for microcrystallites due to electrostatic orientation of amino acid zwitterions by the metal nanoisland film. Moreover, non-additive peaks are observed in the spectrum of the mixture of amino acids adsorbed on SNF, which means that intermolecular interactions between adsorbed amino acids are very significant. The results indicate the need for a thorough analysis of the Raman spectra from amino acid solutions in the presence of a nanostructured metal surface, and may also be of interest for studying molecular properties and intermolecular interactions.

Unmetamorphosed carbonaceous chondrites provide important information concerning the formation and evolution of organic matter, such as amino acids. However, terrestrial contamination remains a valid concern when investigating the organic inventory of meteorites that have fallen to Earth. Accordingly, JAXA’s Hayabusa2 and NASA’s OSIRIS-REx have been launched with the task of returning uncontaminated C-type asteroid material to Earth. The successful Hayabusa2 mission has a very limited sample size (5.4 g). Therefore, many conventional compound specific techniques will struggle to detect amino acids above detection limit with available sample amounts (~several mg to 10’s of mg) being much smaller than those typically used. Here a novel method utilizing ultrahigh performance liquid chromatography-Orbitrap-mass spectrometry is validated and applied to very small meteorite samples, thus providing an approach that can overcome the small sample size constraints of sample return missions. The method is highly sensitive, enabling the detection of amino acids in the carbonaceous chondrites Murchison (2.28 mg) and Orgueil (2.30 mg). Furthermore, quantitation was possible for many of the detected amino acids in Murchison and Orgueil. Using the data presented here, both the amino acid reservoirs of Murchison and Orgueil and the potential application of this method to sample return samples are discussed.

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) pay a role of catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in increased Aβ42:Aβ40 ratio and accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study we performed molecular modeling of APP complex with γ-secretase and analyzed potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures we proposed that APP can form a complex with γ-secretase in 2 potential conformations – M1 and M2. In conformation M1 transmembrane domain of APP forms a contact with perimembrane domain that follows the transmembrane domain 6 (TM6) in PS1 structure. In conformation M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in PS1 structure. By analyzing effects of PS1-FAD mutations on local protein disorder index, we discovered that these mutations increase conformational flexibility of M2 and reduce conformational flexibility of M1. Based on these results we proposed that M2 conformation, but not M1 conformation, of γ secretase complex with APP leads to amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by a curved membranes, such as membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by a relatively flat memranes such as membranes of late endosomes and plasma membrane. These predictions are consistent with published biochemical analysis of APP processing at different subcellular locations. Our results suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting M2 conformation of γ secretase complex with APP.

Amino acid efflux and influx transport systems play vital roles in industrial microorganisms’ cell growth and metabolism. However, although biochemically characterized, most amino acid transporters remain unknown at the molecular level in Bacillus licheniformis. This study focuses on the molecular and functional characterizations of three transporters, YdgF, YvbW, and YveA, mainly when catalyzing the cross-membrane flux of L-Aspartate. When growing in the minimal medium with L-Asp as the only carbon and nitrogen source, the growth of strains lacking proteins YdgF, YvbW, and YveA was significantly inhibited compared with wild-type strains, while supplementing the expression of the corresponding proteins in the single-gene knockout strains can alleviate the inhibition to some extent. Upon overexpression, the recombinant proteins mediate the accumulation of L-aspartate to varying degrees. Compared with wild-type strains, the single knockout strains of the three protein genes exhibited reduced absorption of L-aspartate. In addition, this paper focuses on the effects of these three proteins on the absorption of β-alanine, L-glutamate, D-serine, D-alanine, and glycine.

Soil texture is key information in agriculture for improving soil knowledge and crop performance, so the accurate mapping of this crucial feature is imperative for rationally planning cultivations and for targeting interventions. We studied the relationship between radioelements and soil texture in the Mezzano Lowland (Italy), a 189 km² agricultural plain investigated through a dedicated airborne gamma-ray spectroscopy survey. The K and Th abundances were used to retrieve the clay and sand content by means of a multi-approach method. Linear (simple and multiple) and non-linear (machine learning algorithms with deep neural networks) predictive models were trained and tested adopting a 1:50,000 scale soil texture map. The comparison of these approaches highlighted that the non-linear model introduces significant improvements in the prediction of soil texture fractions. The predicted maps of the clay and of the sand content were compared with the regional soil maps. Although the macro-structures were equally present, the airborne gamma-ray data permits us shedding light on finer features. Map areas with higher clay content were coincident with paleo-channels crossing the Mezzano Lowland in Etruscan and Roman periods, confirmed by the hydrographic setting of historical maps and by the geo-morphological features of the study area.

Peripapillary intrachoroidal cavitation (PICC) is a yellow-orange lesion, located at the outer border of the myopic conus. First described as a localized detachment of the retinal pigment epithelium, its intrachoroidal location was later disclosed, justifying its current name. PICC is related to other myopic complications like posterior staphyloma, but its pathogenesis is not clear to date. Although it has been considered a benign condition, most eyes with PICC show visual field defects, leading to diagnostic uncertainty as these deficits resemble those observed in glaucoma. Furthermore, eyes with PICC can develop macular detachment with retinoschisis. Finally, misdiagnosis of PICC as a metastatic choroidal tumor may lead to unnecessary and anxiety-provoking investigation. Advances in optical coherence tomography (OCT) imaging have improved the visualization of ocular structures, contributing to the understanding of PICC. Recently high optic nerve sheaths traction forces during eye movements in highly myopic eyes have been suggested as promoters of PICC, renewing interest around this condition. However, a review of PICC is still lacking. Therefore, we aimed to provide a concise yet comprehensive overview of the current state of the art, focusing on OCT documentation, pathophysiology and potential future perspectives based on biomechanics of the optic nerve.

The sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys, and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced a marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased the survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53 -/- cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy.

Plant-based diets are increasingly popular for health as well as financial, ethical, and religious reasons. The medical literature clearly demonstrates that plant-based diets can be both nutritionally sufficient and medically beneficial. However, any person on an intentionally restrictive but poorly-informed diet may predispose themselves to clinically-relevant nutritional deficiencies. For persons on a poorly-informed plant-based diet, deficiencies are possible in both macronutrients (protein, essential fatty acids) and micronutrients (vitamin B12, iron, calcium, zinc and vitamin D). Practitioner evaluation of symptomatic patients on a plant-based diet requires special consideration of 7 key nutrient concerns for plant-based diets. This article translates these concerns into 7 practical questions that all practitioners can introduce into their patient assessments and clinical reasoning. Ideally, persons on plant-based diets should be able to answer these 7 questions. Each serves as a heuristic prompt for both clinician and patient attentiveness to a complete diet. As such, these 7 questions support increased patient nutrition knowledge and practitioner capacity to counsel, refer, and appropriately focus clinical resources.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of IDO1, synergism between H pylori and EBV coinfection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs under challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted or supplemented with the 20 proteinogenic AAs, individually and in combinations. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.

To sustain and advance the development of our laboratory, it is imperative for the laboratory 1 personnel to consistently deliver high-quality products and services that meet customer expectations. 2 The progress of productivity and the pace of technological advancements result in constant evolution 3 of measurement procedures, analytical techniques, and overall work methods. Our research within 4 the Neutron Activation Analysis (NAA) laboratory is aimed at contributing to the establishment of 5 quality assurance that complies with the ISO 17025 standard. As such, the laboratory implements 6 quality-oriented approaches to foster a culture of continuous improvement in its detector operations 7 and enhance customer satisfaction.

Flaxseed has been recognized as a valuable source of nutrients and bioactive compounds, including proteins that possess various health benefits. In recent years, studies have shown that flaxseed proteins, including albumins, globulins, glutelin, and prolamins, possess anti-cancer properties. These properties are attributed to their ability to inhibit cancer cell proliferation, induce apoptosis, and interfere with cancer cell signaling pathways, ultimately leading to the inhibition of metastasis. Moreover, flaxseed proteins have been reported to modulate cancer cell mechanobiology, leading to changes in cell behavior and reduced cancer cell migration and invasion. This review provides an overview of the anti-cancer properties of flaxseed proteins, with a focus on their potential use in cancer treatment. Additionally, it highlights the need for further research to fully establish the potential of flaxseed proteins in cancer therapy.

This research investigated the antihypertensive effects of tamarind products and compared their potentials based on their animal model’s data verified by molecular docking, multitarget interactions in network pharmacology, and dynamic simulation assays. The GC-MS characterized tamarind products were administered to the cholesterol-induced hypertensive Wistar albino rat models. Two-week-intervened animals were dissected to collect serum and organs which were respectively subjected to the analyses of hypertension-linked markers and tissue architectures. Lead biometabolites of tamarinds interacted with eight target receptors in molecular docking and dynamic simulation studies and they were tested for multitarget interactions using network pharmacological analyses. Results showed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), C-reactive protein (CRP), Troponin I, and lipid profiles were maximally reinstated by the phenolic-enriched ripened sour over the sweet tamarind flesh extracts, but seed extracts had a smaller influence. Among the tamarind’s biometabolites, Gamma-sitosterol (ϒ-sitosterol) was found to be the best ligand in managing hypertension via the possible ligand-receptor interactions with the guanylate cyclase which displayed the best drug-likeliness through the highest binding energy -9.3 Kcal. Multitargeted interactions-based degree algorithm and phylogenetic tree of pathways showed 14 targeted genes, of which NR3C1, REN, PPARG, and CYP11B1 hub genes, were consistently modulated by the ϒ-sitosterol to reduce hypertension and related risk factors. The dynamic simulation study showed that the P-RMSD values of ϒ-sitosterol-guanylate cyclase were stable between 75.00 to 100.00 ns at the binding pocket. The findings demonstrate that ripened sour tamarind extract may be supplemented to be a more prospective antihypertensive target or nutraceuticals affirming through advanced preclinical and clinical studies.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1a protein and nuclear factor erythroid 2 like 2 (NFE2L2) gene, showed some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1a in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defense, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defense also contributed to that discrimination. A bioinformatic analysis showed that PGC-1a might coordinate the interplay between genes encoding proteins involved in antioxidant defense, senescence and autophagy in the aging retina. These data support importance of PGC-1a in AMD pathogenesis and confirm the utility of mice with PGC-1a knockout as an animal model to study AMD pathogenesis.

The domestic pig (Sus scrofa) is a species representative of the Suina, one of the four suborders within Cetartiodactyla. In this paper, we reported our analysis of the pig TRG locus in comparison with the loci of species representative of the Ruminantia, Tylopoda and Cetacea suborders. The pig TRG genomic structure reiterates the peculiarity of the organization of Cetartiodactyla loci in TRGC “cassettes”, each containing the basic V-J-J-C unit. Eighteen genes arranged in four TRGC cassettes, form the pig TRG locus. All the functional TRG genes were expressed, and the TRGV genes preferentially rearrange with the TRGJ genes within their own cassette, which correlates the diversity of the gamma-chain repertoire with the number of cassettes. Among them, the TRGC5, located at the 5’ end of the locus, is the only cassette that retains a marked homology with the corresponding TRGC cassettes of all the analyzed species. The preservation of the TRGC5 cassette for such a long evolutionary time presumes a highly specialized function of its genes, which could be essential for the survival of species. Therefore, the maintenance of this cassette in pigs confirms that it is the most evolutionarily ancient within Cetartiodactyla, and it has undergone a process of duplication to give rise to the other TRGC cassettes in the different artiodactyl species in a lineage-specific manner.

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine co-releasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play key roles in the regulation of pain, locomotive movement, and respiratory rhythms. Herein, we first describe GABAergic and glycinergic transmission and inhibitory networks, which consist of three types of terminals, in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many of GABAergic neurons convert to co-releasing state. The co-releasing neurons and terminals remain in the dorsal horn, whereas many of co-releasing ones ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

The diagnosis and management of cow's milk allergy (CMA) is a topic of debate and controversy. We aimed to compare the opinions of expert groups from the Middle East (n=14) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n=13). These Expert groups voted on statements developed by the ESPGHAN group and published in a recent position paper. The voting outcome was compared. Overall, there was consensus amongst both groups of experts. Most experts agreed that symptoms of crying, irritability and colic, as single manifestations, do not suggest CMA. They agreed that amino-acid-based formula (AAF) should be reserved for severe cases (e.g. malnutrition and anaphylaxis) and that there is insufficient evidence to recommend a step-down approach. There was no consensus on the statement that a cow’s milk-based extensively hydrolysed formula (eHF) should be the first choice as a diagnostic elimination diet in mild/moderate cases. Although the statements regarding the role of hydrolysed rice formula as a diagnostic and therapeutic elimination diet were accepted, 3/27 disagreed. The votes regarding soy formula highlight the differences in opinion in the role of soy protein in CMA dietary treatment. Generally, soy-based formula is seldom available in the Middle East region. All ESPGHAN experts agreed that there was no added value of probiotics, prebiotics, and synbiotics to the efficacy of elimination diets, whereas 3/14 of the Middle East group thought there was sufficient evidence. Therefore, there is not a consensus on the optimal diagnostic and therapeutic elimination diet for CMA, but the first-choice elimination diet and the stepwise management approach reveal some differences.

The article presents the results of the γ-ray and fast neutrons impact on various rice species, in order to obtain mutant forms resistant to salinity (NaCl) and drought factors (sorbite). They are going to be used as initial forms in synthetic selection when creating varieties, adapted to the stressful conditions of, both, soil and climate in the Kazakhstan Aral Sea. The average lethal doses (LD50) of γ-rays and fast neutrons, as well as, the average NaCl and sorbite lethal concentrations were established. A distinct dependence on the effect of ionizing radiation and stress factors on the number of induced resistant mutant forms has been related to the initial rice variety. The largest number of mutant forms was obtained from the local variety Syr Suluy, followed by Leader and Aikerim varieties. Out of all varieties, only 1% of the initially irradiated by γ-rays seeds survived, while after fast neutron irradiation – 4,3%. M1 mutant plants significantly differ from the initial forms in terms of morphological features – plant height, panicle length, and grain size. They are tolerant to lodging, and have short and highly sterile panicles, indicating that they are mutants.

The root-colonizing endophytic fungus Piriformospora indica promotes root and shoot growth of its host plants. We show that growth promotion of Arabidopsis leaves is abolished when the seedlings are grown on media with nitrogen (N) limitation. The fungus neither stimulated the total N content nor did it promote 15NO3- uptake from agar plates to the leaves of the host under N-sufficient or N-limiting conditions. However, when the roots were co-cultivated with 15N-labelled P. indica, more label can be detected in the leaves of N-starved host plants, but not of plants supplied with sufficient N. Amino acid and primary metabolite profiles, as well as expression analyses of N metabolite transporter genes suggest that the fungus alleviates the adaptation of its host to the N limitation condition. P. indica alters the expression of transporter genes which participate in relocation of NO3-, NH4+ and N metabolites from the roots to the leaves under N limitation. We propose that P. indica participates in the plant´s metabolomic adaptation to N limitation by delivering reduced N metabolites to the host, alleviating metabolic N starvation responses, and reprogramming the expression of N-metabolism related genes.

qNMR is a valuable technique for metrological studies due to the uniformity of its signal response for all chemical species of an isotope of interest, which enables compound-independent calibration. However, protein quantification remained challenging as large molecules produce wide, low-intensity signals that reduce the already low sensitivity. Combining qNMR with the hydrolysis of protein samples into amino acids circumvents many of these issues and facilitates the use of NMR spectroscopy for absolute protein and peptide quantification.In this work, different conditions have been tested for quantifying aromatic amino acids and proteins. First, we examined the pH-based signal shifts in the aromatic region. The preferable pH depends on the selection of the amino acids for quantification and which internal standard substance should be used to avoid peak overlap. Several aromatic compounds, such as terephthalic acid, sulfoisophthalic acid, and benzene tricarboxylic acid, have been applied as internal standards. The quantification of amino acids from an amino acid standard, as well as from a certified reference material (bovine serum albumin), was performed. Using the first two suggested internal standards, recovery was ~ 97 % for histidine, phenylalanine, and tyrosine at a concentration of approximately 1 mM in solution. Acidic hydrolysis of a certified reference material (CRM) of bovine serum albumin (BSA) and subsequent quantification of Phe and Tyr yielded recoveries of 98 ± 2 and 88 ± 4 %, respectively, at a protein concentration of 16 g/L or 250 µM.

γδT have functions of innate and adaptive immunity, with the potential to induce durable responses while being well-tolerated, with limited adverse effects, making it attractive as a tool for immunotherapy. γδT faces challenges as a frontline tool in clinical oncology, with limited response rates due to difficulties in reaching tumor sites with consistent cytotoxic activity and strength. Modulated Electro-hyperthermia (mEHT) is a loco-regional treatment, whereby energy-transmission from an electromagnetic field selectively targets the plasma membrane of tumor cells, inducing apoptosis and activating immune cells. We hypothesized that mEHT could enhance therapeutic effects by drawing γδT to tumor cells, while also rendering tumor cells to be more susceptible to cytotoxic effects. In this study, NOD/SCID mice harboring subcutaneous human HepG2 tumors were treated with intravenous injections of γδT after mEHT treatment. This method increased infiltration of γδT into the tumor site, significantly inhibiting tumor growth as compared to monotherapy with either modality. These data suggest that γδT could mediate a potent anti-tumor effect when combined with mEHT, and provide a strong rationale for combining these modalities in clinical application for cancer treatment.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been linked to changes in amino acid (ΑΑ) levels. The current observational study sought to investigate the relationship between plasma AA concentrations in a NAFLD population and MRI parameters reflecting inflammation and fibrosis, inflammatory and oxidative stress markers, and disease-related anthropometric and biochemical indicators. Approach & Results: Plasma AA levels were quantified with liquid chromatography in 97 NAFLD patients from the MAST4HEALTH study. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers were measured. In total, males and subjects with higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to females and subjects with lower PDFF respectively. Several associations of AAs with disease related markers were revealed, with the more prominent ones being those of aromatic amino acids with log-PDFF (beta: 1.190E-02, p-Value: 0.001) and log-ALT (beta: 7.55E-03, p-Value: 0.001), of branched amino acids with log-insulin (beta: 1.97E-03, p-Value: 1.16E-04) and of ethanolamine (beta: 0.036, p-Value: 3.65E-04) and L-ornithine (beta: 5.4E-04, p-Value: 0.021) with log-total antioxidant status (TAS). Conclusions: Plasma AA levels varied according to sex, BMI, and several MRI clinical factors. Furthermore, significant relationships were demonstrated between AA and several disease indicators, such as MRI parameters, biochemical and oxidative stress indices, showing the potential utility of AAs as diagnostic dis-ease-related indicators activity.

Gold-centered carbene-metal-amides (CMAs) containing cyclic (alkyl)(amino)carbenes (CAACs) are promising emitters for thermally activated delayed fluorescence (TADF). Aiming at design and optimization of new TADF emitters, we report a density functional theory study of over 60 CMAs with various CAAC ligands, systematically evaluating computed parameters in relation to photoluminescence properties. We demonstrate that the efficiency of TADF of CMAs, arising from a compromise of exchange energy and oscillator strength, is governed by the overlap of HOMO and LUMO orbitals, where HOMO is localized on amide and LUMO on Au-carbene. The S0 ground states and excited T1 states of the CMAs adopt approximately coplanar geometries of carbenes and amides, but rotate perpendicular in the excited S1 states, resulting in degeneracy or near-degeneracy of S1 and T1, accompanied with lowering of the S1-S0 oscillator strength from its maximum at coplanar geometries to near zero at rotated geometries. Based on computations, promising new TADF emitters are proposed and synthesized. Bright CMA complex (Et2CAAC)Au(carbazolide) is obtained and fully characterized to demonstrate that high radiative rates up to 106 s-1 can be obtained for the gold-CMA complexes with small CAAC-carbene ligands.

GCN1 is recognized as a factor that is essential for the activation of GCN2, which is a sensor of amino acid starvation. This function is evolutionarily conserved from yeast to higher eukaryotes. However, recent studies have revealed non-canonical functions of GCN1 that are independent of GCN2, such as its participation in cell proliferation, apoptosis, and the immune response, beyond the borders of species. Although it is known that GCN1 and GCN2 interact with ribosomes to accomplish amino acid starvation sensing, recent studies have reported that GCN1 binds to disomes (i.e. ribosomes that collide each other), thereby regulating both the co-translational quality control and stress response. We propose that GCN1 regulates ribosome-mediated signaling by dynamically changing its partners among RWD domain-possessing proteins via unknown mechanisms. We recently demonstrated that GCN1 is essential for cell proliferation and whole-body energy regulation in mice. However, the manner in which ribosome-initiated signaling via GCN1 is related to various physiological functions warrants clarification. GCN1-mediated mechanisms and its interaction with other quality control and stress response signals should be important for proteostasis during aging and neurodegenerative diseases, and may be targeted for drug development.

The article presents research results of the γ-ray and fast neutrons impact on various rice species, in order to obtain mutant forms resistant to salinity (NaCl) and drought factors (sorbitol. They are going to be used as initial forms in synthetic selection when creating varieties, adapted to the stressful conditions of, both, soil and climate in the Kazakhstan Aral Sea. The average lethal doses (LD50) of γ-rays and fast neutrons, as well as the average NaCl and sorbitol lethal concentrations were established. Such environment is best suited for clear manifestation of the mutagenic effect of ionizing radiation and the resistance of rice plants to salinity and drought. A distinct dependence in the effect of ionizing radiation and stress factors on the number of induced resistant mutant forms has been related to the initial rice sort. The largest number of mutant forms was obtained from the local variety Syr Suluy, followed by Leader and AyKerim varieties. From all varieties, the number of mutants obtained from exposure to γ-rays was 43 pieces out of 4500 grains, and from the impact of fast neutrons - 115 pieces out of 2700 grains. M1 mutant plants significantly differ from the initial forms in terms of morphological features – plant height, panicle length, grain size Most plants are characterized by short growth and even dwarfism (˂80 cm). They are lodging tolerant, have short and highly sterile panicles, indicating that they are mutants and resistant to salinity, drought, or both.

The emergence of non-canonical amino acids (ncAAs) has enriched the functional pool inherent in canonical amino acids (cAAs). ncAAs are important building blocks in the production of various pharmaceuticals. The biosynthesis of ncAAs has emerged as an alternative to traditional chemical synthesis because of its environmental friendliness and high efficiency. The breakthrough genetic code expansion (GCE) technique developed in recent years has allowed for the incorporation of ncAAs into target proteins, giving them special functions and biological activities. Biosynthesis of ncAAs and their incorporation into target proteins within a single microbe has become an enticing application of such molecules. Based on that, in this study we first review the biosynthesis methods for ncAAs and analyze the difficulties in biosynthesis. We then summarize the GCE methods and analyze their advantages and disadvantages. Further, we review the application progress of ncAAs and anticipate the challenges and future development directions of ncAAs.

Background: Food waste has been a major social problem in recent years. Annually, 1.3 billion tons of food is wasted worldwide. It is recommended that food waste should be reduced at every stage of production. By-products from food processing have high nutritional value; therefore their use in the design of new products is advisable. Methods: By-products from tomato processing (tomato waste-TW) and pepper (defatted pepper seeds-DPS, pepper placenta-PP) were used at a level of 10-30% to produce extruded pasta. The farinographic characteristics, chemical composition, cooking quality, and color of the pasta were studied. Results: The results showed a significant up to 27% increase in the protein content in the TW30 samples, compared to the control. The TDF content increased over five times in DPS30 and TW30 (27.99% and 25.44%). The amino acid composition of the pasta improved with the fortification, but failed to achieve the complete protein by FAO. The DPS30, PP20, PP30, and all TW samples can be considered high-protein products according to the EU definition (min. 20% energy from protein). Conclusion: Vegetable waste can be a valuable additive for improvement of the nutritional value of food. Their addition is part of the zero-waste trend, which has a positive impact on the environment.

The dentate gyrus (DG) is part of the hippocampal formation and is essential for important cognitive processes such as navigation and memory. The oscillatory activity of the DG network is believed to play a critical role in cognition. DG circuits generate three main rhythms: theta, beta, and gamma, which participate in the specific information processing performed by DG neurons. In the temporal lobe epilepsy (TLE), cognitive abilities are impaired, which may be due to drastic alterations in the DG structure and network activity during epileptogenesis. The theta rhythm and theta coherence are especially vulnerable in dentate circuits; disturbances in DG theta oscillations and their coherence may be responsible for general cognitive impairments observed during epileptogenesis. Some researchers suggested that the vulnerability of DG mossy cells is a key factor in the genesis of TLE, but others did not support this hypothesis. The aim of the review is not only to present the current state of the art in this field of research but to help pave the way for future investigations by highlighting the gaps in our knowledge to completely appreciate the role of DG rhythms in brain functions. Disturbances in oscillatory activity of the DG during TLE development are described in detail that may be a diagnostic marker in the treatment of this disease.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

The integrated stress response is a signaling network comprised of four branches, each of which senses different cellular stressors, converging on the phosphorylation of eIF2α to depress global translation and initiate recovery. One of these branches is composed of GCN2, which senses cellular amino acid insufficiency and participates in the maintenance of amino acid homeostasis. Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is provoked by inhibiting an additional target. In this light, we screened a combination of drugs to identify biologically active compounds which synergize with the GCN2 inhibitor TAP20. First, a panel of 25 compounds was assayed in six cancer cell lines for drug sensitivity. Each compound was then combined with TAP20 at concentrations below their IC50, and the impact on cell growth was assessed. Selected strongly synergistic combinations were further characterised using synergy analyses and matrix-dependent invasion assays. Inhibitors of proteostasis, of the MEK-ERK pathway and pan-CDK inhibitors flavopiridol and seliciclib were found to potently synergize with TAP20 in two of the tested cell lines. Among their common CDK targets is CDK7, which was selectively targeted with THZ-1 and found to synergize with TAP20. Finally, these combinations were found to be partially synergistic when assessed using matrix-dependent invasion assays. However, we found that TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC50. We conclude that GCN2 can be targeted for treating cancers by polytherapy or even monotherapy.

The amino acids (AAs) and vitamins imbalances are observed in celiac disease (CD). This study evaluated the plasma profile of vitamin A and AAs and the expression level of IL-2, IL-4, IL-10, IL-12 and TGFβ in CD patients. A total of 60 children and adults with CD and 40 healthy controls (HCs) were included. Plasma profile of Vitamin A and AAs and the mRNA expression levels of target genes were assessed. Active adult patients exhibited a decrease in Vitamin A levels (p=0.04) and an increase in IL-2 (p=0.008) and IL-12 (p=0.007) mRNA expression compared to HCs. Treated adult patients showed elevated Serine (p=0.003) and Glycin (p=0.04) levels, as well as increased IL-12 (P<0.0001) mRNA expression, and a decrease in Tryptophan (p=0.04) levels relative to the controls. Additionally, treated adult patients had higher plasma levels of Threonine compared to both active (p=0.04) and control (p=0.02) subjects, and increased mRNA expression of IL-4 (p=0.01) in comparison to active patients. In active children with CD, IL-2 mRNA level was found to be higher than in controls (P<0.0001) and in treated children (p=0.005). Treated children with CD exhibited decreased plasma levels of Tryptophan (p=0.01) and Isoleucine (p=0.01) relative to the controls, and increased mRNA expression of TGFβ (p=0.04) relative to active patients. Managing Retinoic acid levels is crucial to alleviate intestinal inflammation of CD patients. Threonine, tryptophan, and Isoleucine are potential therapeutic options for treating CD, and targeting serine, histidine, tyrosine, and aspartate may hold promise as therapeutic targets for CD patients.

The details of the solar flare production mechanisms are not yet completely understood. One of the standing questions is the anisotropy of the X-ray flux, especially in strong flares. It can be studied indirectly by analysing the characteristics of flares at different positions on the visible disc. In this paper, the durations, peak and integral fluxes of strong (X-class) solar flares from cycles 22--25 are considered with respect to their apparent position on the Sun. It is found that there exists a significant north--south asymmetry in all three parameters, which also varies depending on the phase of the solar cycle (with general predominance of the south). This confirms the results of previous studies. A weaker and less significant east--west asymmetry is found as well, partly supported by literature. A previously undetected centre-to-limb asymmetry is reported (in favour of the limb) in all three parameters. All three asymmetries are enhanced during the solar minimum, which could hint at their connection to the large scale magnetic structuring of the Sun. The prevalence of strong solar flares near the limb at the solar minimum has clear space weather warning implications.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, minimum IC50 15.1±0.2 nM) and butyrylcholinesterase (BChE, minimum IC50 5.96±0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability suggesting CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for potential treatment of AD.

Wheat and corn silages are widely used as ruminant feed in Israel due to their availability and cost-effectiveness. To ensure long-term preservation without compromising nutritional quality, effective methods must be employed. Inclusion of additives during harvest and ensiling can enhance efficiency and address preservation challenges. In the current study, the effects of microbial inoculum (MI) and urea on the chemical composition, amino acid profiles, aerobic stability, and in vitro digestibility of wheat and corn silages were investigated. Samples of wheat and corn were subjected to four treatments: control, MI, Urea, and a combination of MI+Urea. The treatments were ensiled in anaerobic conditions and opened after 1, 7, 14, or 28 days. Results showed that additives improved the quality parameters of wheat and corn silages. The inclusion of MI produced the most aerobically stable silages. The inclusion of urea in silages deteriorated aerobic stability. Additives improved in vitro cell wall carbohydrates digestibility in both silages and was the best when MI was combined with urea. These results imply additives could be incorporated in silages to enhance their nutritional value, aerobic stability and digestibility. Nonetheless, increased CP content with additives was not accompanied with parallel increase in amino acids content in corn silage.

The Apetala2/ethylene response factor superfamily refers to a group of transcription factors that share a conserved AP2 DNA binding domain. These factors have been found to have different roles in plant responses to both biotic and abiotic stresses. Samples of hexaploid wheat, tetraploid pasta (or durum wheat), and diploid wheat progenitors were selected. The 29 dehydration-responsive element binding transcription factors in these samples were downloaded from NCBI GenBank for six different countries: Iran, China, Italy, France, Afghanistan, and Azerbaijan. The AP2 domain sequences were identified from the dehydration-responsive element binding transcription factors using PROSITE, ProDom, and SMART software. Next, all sequences were aligned using Multalin and Jalview software. The aligned sequences were then analyzed to identify amino acid locations, types, and frequencies. The multiple alignments showed that approximately 76% of the amino acid residues in the AP2 domains are conserved. According to the amino acid analysis, alanine, serine, and glutamic acid are the most abundant amino acids found in three motifs. The performed phylogenetic analysis illustrates the role of geographical effects on the transcription factor sequences of bread wheat in the Middle East. Significant differences were found between Iranian and Chinese transcription factor sequences. Moreover, genetic variation was observed in the transcription factors of Italian sequences found in pasta and wheat progenitors. Motif structures play a critical role in the domain organization of wheat proteins to enhance the characteristics of assorted metabolic pathways. The structure of the AP2 domain was analyzed by several programs, I-TASSER for instance, to identify the α-helix, β-sheets, and the regions of some significant amino acids in the 3-D model.

Proteins play a pivotal role in supporting athletes by promoting muscle hypertrophy and minimizing protein catabolism during exercise. They stimulate muscle protein synthesis, aiding in the repair of exercise-induced muscle damage and serving as an energy source, particularly for post-exercise glycogen replenishment. In individuals with phenylketonuria (PKU), for whom protein intake is limited to essential phenylalanine (Phe), supplementation with Phe-free amino acids or glycomacropeptides is necessary. Tailored for macronutrient and micronutrient content, these protein substitutes fulfill most protein requirements, but lack Phe, unlike dietary sources of protein. Protein requirements for athletes with PKU exceed general recommendations due to limited availability in supplements and potential catabolism mitigation. Various factors influence tolerated dietary Phe in PKU, including protein substitute quantity, distribution, pharmacological treatment, age, growth rate, pregnancy, catabolic states, and physical activity. While general protein requirements for PKU surpass those of the general population, adherence to supplement regimens is crucial for athletes and patients with PKU. Strategically timed protein substitutes enhance muscle protein synthesis, body composition, and sports performance within safety limits. Individualized intake is essential for optimal outcomes, as proteins have a multifaceted role in optimizing athletic performance and addressing challenges in PKU.

Advanced MRI methods and PET using radiolabeled amino acids provide valuable information in addition to conventional MR imaging for brain tumor diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumor progression from treatment-related changes, and the early assessment of response to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumors. PET is only required in equivocal situations, and spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumors compared with a single modality. This systematic review focuses on studies that were able to demonstrate the additive value of amino acid PET and ‘advanced’ MRI in the diagnosis of brain tumors. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterization of newly diagnosed tumors. However, data concerning the delineation of tumor extent and biopsy guidance are of limited value. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumor recurrence from treatment-related changes. Here, PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of brain tumors, for which hybrid PET/MRI offers optimal conditions.

As the COVID-19 pandemic progresses, new variants of SARS-CoV-2 continue to emerge. This underscores the need to develop optimized tools to study such variants, as well as new coronaviruses that may arise in the future, and to use them for antiviral drug development. Here we introduce microscale thermophoresis (MST) as a reliable and versatile tool for coronavirus research, which we demonstrate through three different applications described in this report: 1) binding of the SARS-CoV-2 spike receptor binding domain (RBD) to peptides as a strategy to prevent virus entry, 2) binding of the RBD to the viral receptor ACE2, and 3) binding of the RBD to ACE2 in complex with the amino acid transporter SLC6A20/SIT1 or its allelic variant rs61731475 (p.Ile529Val). Our results demonstrate that MST is a highly precise approach to study protein-protein and/or protein-ligand interactions in coronavirus research, making it an ideal tool for studying viral variants and developing antiviral agents. The ability to measure interactions with proteins in their near-native plasma membrane environment is a unique advantage of the MST assay over other available binding assays.

Canine mammary tumors (CMTs) are among the most common disease in female dogs and share similarities with human breast cancer, which have placed these animals as a model of study in comparative oncology. Metabolic reprogramming is one of them and is known as a hallmark of carcinogenesis whereby cells undergo adjustments to supply the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as therapeutic strategies which have been tested mostly in human clinical trials, but poorly explored in CMTs. In this dedicated review, we compilated the metabolic changes described for CMTs emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial function. We observed here key factors associated with the presence and aggressiveness of CMTs, such as the increase in glucose uptake followed by enhanced anaerobic glycolysis via upregulation of glycolytic enzymes, changes in glutamine catabolism due to overexpression of glutaminases, raise in fatty acid oxidation and distinct effects depending on the lipid saturation, in addition to mitochondrial DNA which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Some cancer cells rely heavily on non-essential biomolecules for survival, growth, and proliferation. Enzyme based therapeutics can eliminate these biomolecules, thus specifically targeting neoplastic cells; however, enzyme therapeutics are susceptible to immune clearance, exhibit short half-lives, and require frequent administration. Encapsulation of therapeutic cargo within biocompatible and biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) is a strategy for controlled release. Unfortunately, PLGA NPs exhibit burst release of cargo shortly after delivery or upon introduction to aqueous environments where they decompose via hydrolysis. Here we show the generation of hybrid silica-coated PLGA (SiLGA) NPs as viable drug delivery vehicles exhibiting sub-200 nm diameters, a metastable Zeta potential, and high loading efficiency and content. Compared to uncoated PLGA NPs, SiLGA NPs offer greater retention of enzymatic activity and slow the burst release of cargo. Thus, SiLGA encapsulation of therapeutic enzymes, such as asparaginase, could reduce frequency of administration, increase half-life, and improve efficacy for patients with a range of diseases.

Like all RNA viruses, SARS-CoV-2 shows high mutation rate, which has led to the emergence of new variants. Among them, Gamma and Delta developed at the turn of 2020-2021 in Amazonas and India, two ecoregions characterized by hot-humid weather, very similar to that of the summer season due to climate change in Italy, the first Western country to have been hit hard by COVID-19 and to experience lockdown restrictions in a democratic framework of 58,85 million people. Methods: during the state of national health emergency and the Draghi government, the Civil Defense Department daily released the aggregate data coming from the Ministry of Health, the Higher Institute of Health, the Independent Provinces and the Italian Regions, in order to inform about the pandemic situation in Italy. Among these data there were the number of deaths, hospitalizations in intensive care units (ICU), non-ICU patients, contagions, and performed swabs. By means of a team effort, we have collected and elaborated all these data, comparing COVID-19 pandemic in Italy during the summers 2020 (following the nationwide lockdown), 2021 and 2022. Results: from summer 2020 (before mass vaccination) to summers 2021 (after primary mass vaccination) and 2022 (after booster mass vaccination) all pandemic trend indicators have showed a sharp worsening in Italy. COVID-19 deaths increased by ≈298% and ≈834%, ICU hospitalizations by ≈386% and ≈310%, non-ICU hospitalizations by ≈224% and ≈600%, contagions by ≈627% and ≈6.850% (i.e. ≈68,50 times), swabs by ≈354% and ≈370%, and the mean positivity rate passed from ≈1% to ≈2% and ≈20%, respectively. Conclusions: SARS-CoV-2 can be transmitted in any climate, including areas with hot and humid weather, and the emergence of variants adapted to hot-humid climate may result in summer COVID-19 outbreaks, even in neither tropical nor subtropical countries. Although COVID-19 vaccines can confer cross-protection against newly emerging variants, this cross-immunity is obviously not absolute but limited, also taking into account that vaccine protection wanes considerably after 6 months. It follows that a subject vaccinated at the beginning of winter will not be completely covered in the height of summer, without forgetting the unvaccinated. As a final remark, the long nationwide lockdown made it possible to flatten SARS-CoV-2 circulation and, therefore, its negative impact on Italy during summer 2020.

The liver performs a fundamental role in the regulation of diverse physiological processes. Despite enormous advances in modern medicine, there are no completely effective drugs that stimulate hepatic function, offer complete protection to the organ, or aid in regenerating hepatic cells. Thus, it is necessary to identify alternative plant-origin pharmaceuticals more effective and less toxic for the treatment of hepatic diseases. The aim of this research was to establish the chemical composition of the American cranberry (Oxycoccus macrocarpus) leaves extract and its aminoacids preparations as well as their hepatoprotective activity. 19 phenolic compounds (8 flavonoids (flavones and flavonols), 4 anthocyanins, 2 catechins, and 3 hydroxycinnamic acids) and main amino acids (valine, arginine, glycine, histidine, aspartic acid, and taurine) were identified and quantified in the American cranberry (O. macrocarpus) leaves extract and its 7 aminoacids preparations. The therapeutic and prophylactic consumption of the American cranberry leaves extracts led to a decrease in the intensity of the lipid peroxidation process compared to the control pathology group in the experiment of acute toxic damage to the liver by tetrachloromethane on rats. The most pronounced hepatoprotective activity was established for the American cranberry leaves extracts’ preparations with arginine and valine.

Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are 6 species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD disease pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically-contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post treatment. To assess the interferon stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ were evaluated. Secreted ISGs blocked recombinant VSV expressing EBOV GP (rVSV/EBOV GP) infection, but failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

Gamma-aminobutyric acid (GABA), a non-protein-producing amino acid, is extensively found in microorganisms, plants and vertebrates, and is abundantly expressed in the spinal cord and brain. To date, GABA is considered to be the major inhibitory neurotransmitter in the central nervous system. Its physiological effects are related to the regulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of insomnia and depres-sion. Mediated through its specific receptors, it plays a pivotal role in the control of neuronal ex-citability, which can serve as anovel target for developing analgesics for pain management. This review provides an update on the accumulating evidence of specific GABA receptors and their subtypes in the involvement of pain analgesia.

With the development of nuclear technology application, radiation safety has been widely concerned, and there is an urgent need for novel shielding materials. Among the various options available, non-lead organic composite shielding material has emerged as a promising solution in the field of radiation shielding due to its high strength, easy processing, and light weight. In this study, tungsten/epoxy resin (W/EP) composite samples with tungsten weight fraction from 0% to 60% were prepared. The shielding and mechanical properties of W/EP composites were investigated. The results show that the results showed that the higher the tungsten content, the greater the shielding capacity of W/EP composites, particularly for low-energy gamma ray (γ) shielding. However, the addition of tungsten reduces the impact strength and tensile properties of the material. Overall, for 300 keV γ-ray, W/EP with 30% tungsten content has comparable shielding capacity to ordinary concrete. W/EP composite materials can serve as shielding materials for low-energy γ-rays.

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine’s anticancer activity together with that of three other bisindoles - conophylline, leucophyllidine and bipleiophylline against human-derived carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (as observed in MDA-MB-468 breast cancer cells) or senescence (as detected in HT-29 colorectal carcinoma cells). Annexin V-FITC/PI, caspase activation and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Evident cell cycle perturbations were observed comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed induction of aberrant mitotic phenotypes - multi-nucleation, membrane blebbing and DNA-fragmentation. The DNA integrity assessment of HCT-116 and MDA-MB-468 showed irreparable damage identified by increased fluorescent γ-H2AX during the G1 cell cycle phase. Furthermore, γ-H2AX foci were visually validated in HCT-116 and MDA-MB-468 cells using confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by NQO1 expression. Collectively, we present conofolidine as a potential anticancer candidate capable of inducing heterogeneous modes of cancer cell death in vitro, encouraging further preclinical evaluation of this natural product.

46 patients with a newly diagnosed, histologically verified glioma that was visually classified as [18F]FET-negative were included. Tumor volumes were defined using routine T2/FLAIR MRI data and applied to extract information from dynamic [18F]FET PET data, i.e. early and late tu-mor-to-background (TBR5-15, TBR20-40) images and time-to-peak (TTP) images. Radiomic features of healthy background were calculated from the tumor volume-of-interest mirrored to the con-tralateral hemisphere. Differences between tumor and healthy tissue features were compared us-ing Wilcoxon test. Additionally, the ability to distinguish tumor from healthy tissue was assessed using logistic regression. 5 % of features derived from TBR20-40 images were significantly differ-ent; 16 % of features derived from TBR5-15 images and 69 % of features derived from TTP images. The high number of significantly different features derived from TTP images was even found in isometabolic gliomas (after exclusion of photopenic gliomas) with visually normal [18F]FET up-take in static images. However, the differences did not reach satisfactory predictability for ma-chine learning based identification of tumor tissue. In conclusion, radiomic features derived from dynamic [18F]FET PET data may extract additional information even in [18F]FET-negative glio-mas, which should be investigated in larger cohorts and correlated with histological and out-come features in future studies.

The G-NUMEN array is the future gamma spectrometer of the NUMEN experiment (Nuclear Matrix Element for the Neutrinoless double beta decay), to be installed around the object point of the MAGNEX magnetic spectrometer at the INFN-LNS laboratory.. This project aims at exploring Double Charge Exchange (DCE) reactions in order to obtain crucial information about the neutrinoless double beta decay (0νββ). The primary objective of the G-NUMEN array is to detect the gamma rays emitted from the de-excitation of the excited states populated via DCE reactions with good energy resolution and detection efficiency, amidst a background composed of transitions from competingreaction channels with far higher cross-sections. To achieve this, the G-NUMEN signalswill be processed in coincidence with those generated by the detection of the reaction ejectiles in the MAGNEX Focal Plane Detector(FPD). Under the expected experimental conditions, G-NUMEN detectors will operate at high counting rates, of the order of hundreds of kHz per detector, while maintaining excellent energy and timing resolutions. The complete array will consist of over 100 LaBr3(Ce) scintillators. Initial tests have been conducted on the first detectors of the array, allowing for the determination of their performance at high rates.

Additive manufacturing or 3D printing applying polycaprolactone-(PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the most suitable gamma radiation conditions to sterilize PCL-based scaffolds in a preliminary biocompatibility assessment, envisioning future studies for airway obstruction conditions. Three radiation levels were considered, 25 kGy, 35 kGy and 45 kGy and evaluated as to their cyto- and biocompatibility. All three groups presented biocompatible properties, indicating an adequate sterility condition. As for the cytocompatibility analysis, devices sterilized by 35 kGy and 45 kGy showed better results, with the 45 kGy showing overall improved outcomes. This study allowed to select the most suitable sterilization condition for PCL-based scaffolds, aiming at immediate future assays, by applying 3D-customized printing techniques to specific airway obstruction lesions of the trachea.

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-Covid-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of Mannose Receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of Covid-19 pathology and immunity to SARS-CoV-2.

A 4×2 factorial experiment was conducted to evaluate the potential of feeding dietary gamma-oryzanol and vitamin E tocotrienols in hens reared in 840 (low cage density; LCD) or 420 cm2/hen (high cage density; HCD). A total of 120 hens were allocated into eight groups with five replicates. Diets were a control (CON) or the control diet supplemented with 200 ppm gamma-oryzanol (GO-200), 200 ppm vitamin E tocotrienols (VE-200) or 200 ppm gamma-oryzanol + 200 ppm vitamin E tocotrienols (GE-400). Results showed that HCD-housed hens decreased (P < 0.01) egg performance and quality. Average egg weight (AEW), egg mass and FCR improved in all supplemented treatments. Results on the AEW, FCR, and eggshell qualities of birds kept at the HCD revealed the best responses in the GE-400 group (P < 0.01). Among hens kept on an HCD, there was a noticeable decrease in HMGCR mRNA abundance in the VE-200 group, while the highest IFN-γ mRNA abundance was found in hens fed the GO-200 diet (P < 0.05). Thus, this study suggested that dietary GO or VE at 200 ppm either individually or in combination could improve performance and egg quality as well as regulate the abundance of immune- and stress-related genes.

Serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome with growth deficit, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP-loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-amino-levulinic-acid synthase (ALAS) to promote pyridoxal-phosphate (PLP) binding. CLPX may influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted arginine/histidine reduction. In Mus musculus cerebellum, reductions of Arginine/Histidine and Citrulline occurred with concomitant accumulation of heme-precursor protoporphyrin-IX. This suggests that increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA with C1 glycine but also specific C5 delta amino-acids. As responsible enzymes for these converse effects, elevated abundance of CLPX and ALAS is paralleled by elevation of OAT (PLP-dependent, ornithine-delta-aminotransferase). Possibly as consequence of altered C1 metabolism, CLPP-null cells in P. anserina proteome profiles showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. Reduced Histidine levels may explain previously observed metal interaction problems. As main nitrogen-storing metabolite, deficient Arginine would affect the urea cycle and polyamine synthesis. Supplementation of Arginine and Histidine might rescue growth deficits of CLPP-mutant patients.

Abstract: Cancer cells are originated by normal cells and with those share the need to be fed. Metabolic reprogramming in cancer cells is not yet fully understood although there is a vast literature suggesting that huge amounts of both energy and substrates are require for synthesis of components of new neoplastic cells so that any macronutrient may be efficiently utilized. Recently, in vitro data show that EAA supplementation promoted colon cancer cells apoptosis by enhanced autophagy. Therefore, in this study we tested in vivo the effects of matched macronutrients standard laboratory diet (control) versus EAA rich modified diet (EAArmd) in mice injected with colon cancer cells. Results of the first set of 12 animals, 6 controls and 6 EAArmd-fed, showed that controls mice develop cancer volume cancers 5 times larger and heavier than EAArmd-fed. If confirmed, these results would open new scenarios for the cancer integrate therapies.

Ribotoxin-like proteins (RL-Ps) are specific ribonucleases found in mushrooms that are able to cleave a single phosphodiester bond located in the Sarcin-Ricin Loop (SRL) of the large rRNA. The cleaved SRL interacts differently with some ribosomal proteins (P-stalk). This action blocks protein synthesis because the damaged ribosomes are unable to interact with elongation factors. Here, the amino acid sequence of eryngitin 3 and 4, RL-Ps isolated from Pleurotus eryngii fruiting bodies, was determined to: i) obtain structural information on this specific ribonuclease family from edible mushrooms; and ii) explore the structural determinants which justify their different biological and antipathogenic activities. Indeed, eryngitin 3 (exhibited higher toxicity with respect to eryngitin 4 against tumoral cell lines and model fungi. Structurally, eryngitin 3 and 4 consist of 132 amino acids, most of them identical and exhibit a single free cysteinyl residue. The amino acidic differences between the two toxins are: i) an additional phenylalanyl residue at the N-terminus of eryngitin 3, not retrieved in eryngitin 4; and ii) an additional arginyl residue at C-terminus of eryngitin 4, not retrieved in eryngitin 3. The 3D-models of eryngitins show slight differences at the N- and C-terminal regions. In particular, the positive electrostatic surface at C-terminal of eryngitin 4 is due to the additional arginyl residue not retrieved in eryngitin 3. This additional positive charge could interfere with the binding to the SRL (substrate) or with some ribosomal proteins (P-stalk structure), during substrate recognition.