Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs).
Methods
We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation.
Results
NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations.
Discussion
Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.
Aberrant protein aggregation jeopardizes cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer's disease (AD) and Huntington's disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44 protein, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both; the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable for the development of several disorders including HD, while minimally affecting lifespan. This protection was dependent on the activity of aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modifies signaling pathways, thereby modulating the expression of various genes, including these, which are known as protein homeostasis (proteostasis) regulators such as txt-13 and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.
Taste dysfunctions may occur, for example, after viral infection, surgery, medications, or with age. In clinical practice, it is important to assess patients’ taste function with rapidity and reliability. This study aimed to develop a test that assesses human gustatory sensitivity together with somatosensory functions of astringency and spiciness. A total of 154 healthy subjects and 51 patients with chemosensory dysfunction rated their gustatory sensitivity. They underwent a whole-mouth identification test of 12 filter-paper strips impregnated with low and high concentrations of sweet, sour, salty, bitter (sucrose, citric acid, NaCl, quinine), astringency (tannin), and spiciness (capsaicin). The percentage of correct identifications for high-concentrated sweet and sour, and for low-concentrated salty, bitter and spicy was lower in patients as compared with healthy participants. Interestingly, a lower identification in patients for both astringent concentrations was found. Based on the results, we proposed the Seven-iTT to assess chemo/somatosensory function, with a cut-off of 6 out of 7. The test score discriminated patients from healthy controls and showed gender differences among healthy controls. This quantitative test seems to be suitable for routine clinical assessment of gustatory and trigeminal function. It also provides new evidence on the mutual interaction between the two sensory systems.
The problem of tunneling ionization and the associated questions of how long it takes for an electron to tunnel through the barrier, and what the tunneling rate has fascinated scientists for almost a century. In strong field physics, tunnel ionization plays an important role, and accurate knowledge of the time-dependent tunnel rate is of paramount importance. The Keldysh theory and other more advanced related theories are often used, but their accuracy is still controversial. In previous work, we suggested using a curved waveguide as a quantum simulator to simulate the tunnel ionization process. Here we implemented for the first time such a curved waveguide and observed the simulated tunneling ionization process. We compare our results with the theory.
Phosphide-based nanocrystals (NCs), including InP and Cu3–xP, are relevant for applications in light-emitting devices and catalysis, yet their synthetic design is limited in terms of size range and homogeneity. We report the synthesis of uniform and size-controlled emissive wurtzite-phase InP NCs formed via cation exchange from Cu3–xP. First, size-controlled Cu3–xP NCs are synthesized by the formation of metallic Cu0 NCs and their phosphidation to Cu3–xP. By changing the ligands and precursor concentrations, the NC size is varied between 5 and 13 nm. Using cation exchange, InP NCs are then generated. As the surface of InP NCs is prone to oxidation and defects that decrease their emission, we performed a reaction with NOBF4. This yields InP NCs with resolved absorption features and efficient band-gap emission as a result of impurity removal and surface passivation. The effect of water, acid, and halides on the balance of NC etching and surface passivation is studied. With this approach, high-quality wurtzite InP NCs are obtained while the emission is tuned between 810 and 600 nm. The obtained NCs are potential building blocks for catalytic and optoelectronic applications.
Times of emergency often serve as triggers for the creation of new policy. Such policies may involve restriction of human rights, and various mechanisms can be used to mitigate the severity of such restrictions. One such mechanism is the temporary measure. A series of three experiments examined the potential of temporary measures for increasing the likelihood of approval of rights-restricting policy and the role of time – both prospectively and retrospectively – in the willingness to restrict human rights. We find that behavioural examination confirms the concerns expressed in the literature regarding temporary legislation. Participants asked to approve a rights-restricting policy were more willing to approve a temporary measure when it was presented as a compromise, and they were more willing to extend a rights-restricting policy when it had previously been implemented. These findings indicate a possible slippery slope effect in temporary legislation: policymakers might be persuaded to approve measures they would not otherwise approve when those measures are temporary or when they have been previously approved by others.
Michal Bar-Oz, Martini, Maria Carla, Alonso, Maria Natalia, Meir, Michal , Lore, Nicola Ivan, Miotto, Paolo , Riva, Camilla , Angala, Shiva K, Xiao, Junpei , Masiello, Catherine S, Misiakou, Maria Anna, Sun, Huaming , Moy, Justin K, Jackson, Mary , Johansen, Helle Krogh, Cirillo, Daniela Maria, Shell, Scarlet S, ו Barkan, Daniel . 2023. “The Small Non-Coding Rna B11 Regulates Multiple Facets Of Mycobacterium Abscessus Virulence”. Plos Pathogens, 19. doi:10.1371/journal.ppat.1011575. תקציר
Mycobacterium abscessus causes severe disease in patients with cystic fibrosis. Little is known in M. abscessus about the roles of small regulatory RNAs (sRNA) in gene regulation. We show that the sRNA B11 controls gene expression and virulence-associated phenotypes in this pathogen. B11 deletion from the smooth strain ATCC_19977 produced a rough strain, increased pro-inflammatory signaling and virulence in multiple infection models, and increased resistance to antibiotics. Examination of clinical isolate cohorts identified isolates with B11 mutations or reduced expression. We used RNAseq and proteomics to investigate the effects of B11 on gene expression and test the impact of mutations found in clinical isolates. Over 200 genes were differentially expressed in the deletion mutant. Strains with the clinical B11 mutations showed expression trends similar to the deletion mutant, suggesting partial loss of function. Among genes upregulated in the B11 mutant, there was a strong enrichment for genes with B11-complementary sequences in their predicted ribosome binding sites (RBS), consistent with B11 functioning as a negative regulator that represses translation via base-pairing to RBSs. Comparing the proteomes similarly revealed that upregulated proteins were strongly enriched for B11-complementary sequences. Intriguingly, genes upregulated in the absence of B11 included components of the ESX-4 secretion system, critical for M. abscessus virulence. Many of these genes had B11-complementary sequences at their RBSs, which we show is sufficient to mediate repression by B11 through direct binding. Altogether, our data show that B11 acts as a direct negative regulator and mediates (likely indirect) positive regulation with pleiotropic effects on gene expression and clinically important phenotypes in M. abscessus. The presence of hypomorphic B11 mutations in clinical strains is consistent with the idea that lower B11 activity may be advantageous for M. abscessus in some clinical contexts. This is the first report on an sRNA role in M. abscessus.
yet their synthetic design is limited in terms of size range and homogeneity. We report the synthesis of uniform and size-controlled emissive wurtzite-phase InP NCs formed via cation exchange from Cu3–xP. First, size-controlled Cu3–xP NCs are synthesized by the formation of metallic Cu0 NCs and their phosphidation to Cu3–xP. By changing the ligands and precursor concentrations, the NC size is varied between 5 and 13 nm. Using cation exchange, InP NCs are then generated. As the surface of InP NCs is prone to oxidation and defects that decrease their emission, we performed a reaction with NOBF4. This yields InP NCs with resolved absorption features and efficient band-gap emission as a result of impurity removal and surface passivation. The effect of water, acid, and halides on the balance of NC etching and surface passivation is studied. With this approach, high-quality wurtzite InP NCs are obtained while the emission is tuned between 810 and 600 nm. The obtained NCs are potential building blocks for catalytic and optoelectronic applications.