Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo

Inhibition of Bifidobacterium SP Isolated From Infants Feces Towards Adhesion of Salmonella Typhi on Balb/c Mice Enterocyte

Diarrhea, up to the recent year remains a cause of high morbidity and mortalityworldwide, especially in developing countries including Indonesia. Research concerning ofmanagement, prevention, and medication of the disease have been continually improved. Theaim of this research is searching Bifidobacterium sp isolated from infants feces. ThisBifidobacterium was then applied as an anti-adhesion of Salmonella typhi in the hope to gain acure of diarrhea. This research employed two research designs, namely descriptive explorationand true experimental. Exploration was applied in order to obtain isolation and characterizationof Bifidobacterium isolated from infants feces. Adherence ability of this Bifidobacterium sptowards Salmonella typhi adhesion on mice entherocyte was then carried out by applyingRandomized Posttest-Only Control Group Design. In this research, average Bifidobacterium spadhesion index of 1950 on entherocyte was obtained. In simple word, there are 19.5Bifidobacteria adhere to any single entherocyte cell. This adhesion index value is highercompare to Salmonella typhi adhesion of 1504. Conclusions that can be drawn from this researchare the finding of Bifidobacterium sp isolated from infants feces. This Bifidobacterium sp has anability to inhibit adhesion of Salmonella typhi on BALB/c mice enterocyte. Future work that canbe carried out are further researches concerning whether these bacteria have an ability to inhibitadherence of other pathogen bacteria. More over, searching of cell wall adhesin ofBifidobacterium sp that can be used as a replacement of life probiotic bacteria is also a greatinterest of research to be carried out

Sequential presentation protects working memory from catastrophic interference

Neural network models of memory are notorious for catastrophic interference: old items are forgotten as new items are memorized (e.g., French, 1999; McCloskey & Cohen, 1989). While Working Memory (WM) in human adults shows severe capacity limitations, these capacity limitations do not reflect neural-network style catastrophic interference. However, our ability to quickly apprehend the numerosity of small sets of objects (i.e., subitizing) does show catastrophic capacity limitations, and this subitizing capacity and WM might reflect a common capacity. Accordingly, computational investigations (Knops, Piazza, Sengupta, Eger, & Melcher, 2014; Sengupta, Surampudi, & Melcher, 2014) suggest that mutual inhibition among neurons can explain both kinds of capacity limitations as well as why our ability to estimate the numerosity of larger sets is limited according to a Weber ratio signature. Based on simulations with a saliency map-like network and mathematical proofs, we provide three results. First, mutual inhibition among neurons leads to catastrophic interference when items are presented simultaneously. The network can remember a limited number of items, but when more items are presented, the network forgets all of them. Second, if memory items are presented sequentially rather than simultaneously, the network remembers the most recent items rather than forgetting all of them. Hence, the tendency in WM tasks to sequentially attend even to simultaneously presented items might not only reflect attentional limitations, but an adaptive strategy to avoid catastrophic interference. Third, the mean activation level in the network can be used to estimate the number of items in small sets, but does not accurately reflect the number of items in larger sets. Rather, we suggest that the Weber ratio signature of large number discrimination emerges naturally from the interaction between the limited precision of a numeric estimation system and a multiplicative gain control mechanism

PARP inhibition: a promising therapeutic target in ovarian cancer

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane -based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer

Neural correlates of intentional and stimulus-driven inhibition: a comparison

People can inhibit an action because of an instruction by an external stimulus, or because of their own internal decision. The similarities and differences between these two forms of inhibition are not well understood. Therefore, in the present study the neural correlates of intentional and stimulus-driven inhibition were tested in the same subjects. Participants performed two inhibition tasks while lying in the scanner: the marble task in which they had to choose for themselves between intentionally acting on, or inhibiting a prepotent response to measure intentional inhibition, and the classical stop signal task in which an external signal triggered the inhibition process. Results showed that intentional inhibition decision processes rely on a neural network that has been documented extensively for stimulus-driven inhibition, including bilateral parietal and lateral prefrontal cortex and pre-supplementary motor area. We also found activation in dorsal frontomedian cortex and left inferior frontal gyrus during intentional inhibition that depended on the history of previous choices. Together, these results indicate that intentional inhibition and stimulus-driven inhibition engage a common inhibition network, but intentional inhibition is also characterized by additional context-dependent neural activation in medial prefrontal cortex

Event-related brain potentials in the study of inhibition: cognitive control, source localization and age-related modulations

In the previous 15 years, a variety of experimental paradigms and methods have been employed to study inhibition. In the current review, we analyze studies that have used the high temporal resolution of the event-related potential (ERP) technique to identify the temporal course of inhibition to understand the various processes that contribute to inhibition. ERP studies with a focus on normal aging are specifically analyzed because they contribute to a deeper understanding of inhibition. Three time windows are proposed to organize the ERP data collected using inhibition paradigms: the 200 ms period following stimulus onset; the period between 200 and 400 ms after stimulus onset; and the period between 400 and 800 ms after stimulus onset. In the first 200 ms, ERP inhibition research has primarily focused on N1 and P1 as the ERP components associated with inhibition. The inhibitory processing in the second time window has been associated with the N2 and P3 ERP components. Finally, in the third time window, inhibition has primarily been associated with the N400 and N450 ERP components. Source localization studies are analyzed to examine the association between the inhibition processes that are indexed by the ERP components and their functional brain areas. Inhibition can be organized in a complex functional structure that is not constrained to a specific time point but, rather, extends its activity through different time windows. This review characterizes inhibition as a set of processes rather than a unitary process

The temporal dynamic of response inhibition in early childhood: An ERP study of partial and successful inhibition

Event-related potentials were recorded while five-year-old children completed a Go/No-Go task that distinguished between partial inhibition (i.e., response is initiated but cancelled before completion) and successful inhibition (i.e., response is inhibited before it is initiated). Partial inhibition trials were characterized by faster response initiation and later latency of the lateral frontal negativity (LFN) than successful Go and successful inhibition trials. The speed of response initiation was influenced by the response speed on previous trials and influenced the response speed on subsequent trials. Response initiation and action decision dynamically influenced each other, and their temporal interplay determined response inhibition success

The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABA_A receptor-mediated inhibition

Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described ‘spillover’ mode of inhibition, generated by the dynamic recruitment of extrasynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (α1β2γ2) and extrasynaptic (α4β2δ) GABA(A)Rs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (α1(0/0)) or extrasynaptic (δ(0/0)) GABA(A)Rs. Etomidate (3 μm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABA(A)Rs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABA(A)Rs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states

Inhibiting the inhibition

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects