This study was designed to evaluate the oxidative damage, genotoxicity, and DNA damage in the liver of rats treated with titanium nanoparticles (TiO-NPs) with an average size of 28.0 nm and ξ-potential of - 33.97 mV, and to estimate the protective role of holy basil essential oil nanoemulsion (HBEON). Six groups of Male Sprague-Dawley rats were treated orally for 3 weeks as follows: the control group, HBEO or HBEON-treated groups (5 mg/kg b.w), TiO-NPs-treated group (50 mg/kg b.w), and the groups treated with TiO-NPs plus HBEO or HBEON. Samples of blood and tissues were collected for different analyses. The results revealed that 55 compounds were identified in HBEO, and linalool and methyl chavicol were the major compounds (53.9%, 12.63%, respectively). HBEON were semi-round with the average size and ζ-potential of 120 ± 4.5 nm and - 28 ± 1.3 mV, respectively. TiO-NP administration increased the serum biochemical indices, oxidative stress markers, serum cytokines, DNA fragmentation, and DNA breakages; decreased the antioxidant enzymes; and induced histological alterations in the liver. Co-administration of TiO-NPs plus HBEO or HBEON improved all the tested parameters and the liver histology, and HBEON was more effective than HBEO. Therefore, HEBON is a promising candidate able to protect against oxidative damage, disturbances in biochemical markers, gene expression, DNA damage, and histological changes resulting from exposure to TiO-NPs and may be applicable in the food and pharmaceutical sectors.

Acquiring reliable knowledge amidst uncertainty is a topical issue of modern science. Interval mathematics has proved to be of central importance in coping with uncertainty and imprecision. Algorithmic differentiation, being superior to both numeric and symbolic differentiation, is nowadays one of the most celebrated techniques in the field of computational mathematics. In this connexion, laying out a concrete theory of interval differentiation arithmetic, combining subtlety of ordinary algorithmic differentiation with power and reliability of interval mathematics, can extend real differentiation arithmetic so markedly both in method and objective, and can so far surpass it in power as well as applicability. This article is intended to lay out a systematic theory of dyadic interval differentiation numbers that wholly addresses first and higher order automatic derivatives under uncertainty. We begin by axiomatizing a differential interval algebra and then we present the notion of an interval extension of a family of real functions, together with some analytic notions of interval functions. Next, we put forward an axiomatic theory of interval differentiation arithmetic, as a two-sorted extension of the theory of a differential interval algebra, and provide the proofs for its categoricity and consistency. Thereupon, we investigate the ensuing structure and show that it constitutes a multiplicatively non-associative S-semiring in which multiplication is subalternative and flexible. Finally, we show how to computationally realize interval automatic differentiation. Many examples are given, illustrating automatic differentiation of interval functions and families of real functions.

Acquiring reliable knowledge amidst uncertainty is a topical issue of modern science. Interval mathematics has proved to be of central importance in coping with uncertainty and imprecision. Algorithmic differentiation, being superior to both numeric and symbolic differentiation, is nowadays one of the most celebrated techniques in the field of computational mathematics. In this connexion, laying out a concrete theory of interval differentiation arithmetic, combining subtlety of ordinary algorithmic differentiation with power and reliability of interval mathematics, can extend real differentiation arithmetic so markedly both in method and objective, and can so far surpass it in power as well as applicability. This article is intended to lay out a systematic theory of dyadic interval differentiation numbers that wholly addresses first and higher order automatic derivatives under uncertainty. We begin by axiomatizing a differential interval algebra and then we present the notion of an interval extension of a family of real functions, together with some analytic notions of interval functions. Next, we put forward an axiomatic theory of interval differentiation arithmetic, as a two-sorted extension of the theory of a differential interval algebra, and provide the proofs for its categoricity and consistency. Thereupon, we investigate the ensuing structure and show that it constitutes a multiplicatively non-associative S-semiring in which multiplication is subalternative and flexible. Finally, we show how to computationally realize interval automatic differentiation. Many examples are given, illustrating automatic differentiation of interval functions and families of real functions.

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.

Cernunnos deficiency is a rare genetic disorder characterized by immunodeficiency, microcephaly, growth retardation, bird-like facies, sensitivity to ionizing radiation, few autoimmune manifestations, premature aging of hematopoietic stem cells at an early age, and occasional myeloproliferative disease. Herein we present five Egyptian Cernunnos patients from 3 different families. We describe the patients' clinical phenotypes, their immunological profile as well as genetic results. Sequence analysis revealed three different mutations in the NHEJ1 gene: a nonsense variant c.532C > T; p.(Arg178Ter), an intronic variant c.178-1G > A and a frameshift insertion variant c.233dup; p.(Asn78LysfsTer14). In conclusion, Cernunnos deficiency can have a wide range of clinical features. The characteristic immune profile including a decrease in recent thymic emigrants and naive T cells, markedly elevated memory T cells together with normal to high IgM, and a decrease in IgG and IgA. This immune profile is highly suggestive of Cernunnos deficiency in T-B-NK + SCID patients especially surviving for older ages.

Sperm heterogeneity creates challenges for successful artificial insemination. Seminal plasma (SP) surrounding sperm is an excellent source for detecting reliable non-invasive biomarkers of sperm quality. Here, we isolated microRNAs (miRNAs) from SP-derived extracellular vesicles (SP-EV) of boars with divergent sperm quality statuses. Raw semen from sexually mature boars was collected for eight weeks. Sperm motility and normal morphology were analyzed, and the sperm was classified as poor- or good-quality based on standard cutoffs of 70% for the parameters measured. SP-EVs were isolated by ultracentrifugation and confirmed by electron microscopy, dynamic light scattering, and Western immunoblotting. The SP-EVs were subjected to total exosome RNA isolation, miRNA sequencing, and bioinformatics analysis. The isolated SP-EVs were round spherical structures approximately 30–400 nm in diameter expressing specific molecular markers. miRNAs were detected in both poor- (n = 281) and good (n = 271)-quality sperm, with fifteen being differentially expressed. Only three (ssc-miR-205, ssc-miR-493-5p, and ssc-miR-378b-3p) allowed gene targeting associated with cellular localization (nuclear and cytosol) and molecular functions (acetylation, Ubl conjugation, and protein kinase binding), potentially impairing sperm quality. PTEN and YWHAZ emerged as essential proteins for protein kinase binding. We conclude that SP-EV-derived miRNAs reflect boar sperm quality to enable therapeutic strategies to improve fertility.

Huntington's disease is a neurodegenerative, trinucleotide repeat (TNR) disorder affecting both males and females. It is caused by an abnormal increase in the length of CAG•CTG TNR in exon 1 of the gene (). The resultant, mutant HTT mRNA and protein cause neuronal toxicity, suggesting that reduction of their levels would constitute a promising therapeutic approach. We previously reported a novel strategy in which chemically modified oligonucleotides (ONs) directly target chromosomal DNA. These anti-gene ONs were able to downregulate both mRNA and protein. In this study, various locked nucleic acid (LNA)/DNA mixmer anti-gene ONs were tested to investigate the effects of varying ON length, LNA content, and fatty acid modification on expression. Altering the length did not significantly influence the ON potency, while LNA content was critical for activity. Utilization of palmitoyl-modified LNA monomers enhanced the ON activity relatively to the corresponding nonmodified LNA under serum starvation conditions. Furthermore, the number of palmitoylated LNA monomers and their positioning greatly affected ON potency. In addition, we performed RNA sequencing analysis, which showed that the anti-gene ONs affect the "immune system process, mRNA processing, and neurogenesis." Furthermore, we observed that for repeat containing genes, there is a higher tendency for antisense off-targeting. Taken together, our findings provide an optimized design of anti-gene ONs that could potentially be developed as DNA-targeting therapeutics for this class of TNR-related diseases.