Stuttered swallowing: Electric stimulation of the right insula interferes with water swallowing. A case report

<p>Abstract</p> <p>Background</p> <p>Various functional resonance imaging, magnetoencephalographic and lesion studies suggest the involvement of the insular cortex in the control of swallowing. However, the exact location of insular activation during swallowing and its functional significance remain unclear.</p> <p>Case presentation</p> <p>Invasive electroencephalographic monitoring was performed in a 24-year-old man with medically intractable stereotyped nocturnal hypermotor seizures due to a ganglioglioma. During stimulation of the right inferior posterior insular cortex with depth electrodes the patient spontaneously reported a perception of a "stutter in swallowing". Stimulation of the inferior posterior insular cortex at highest intensity (4 mA) was also associated with irregular and delayed swallows. Swallowing was not impaired during stimulation of the superior posterior insular cortex, regardless of stimulation intensity.</p> <p>Conclusions</p> <p>These results indicate that the right inferior posterior insular cortex is involved in the neural circuitry underlying the control of swallowing.</p

Cyclin-Dependent Kinase Activity Controls the Onset of the HCMV Lytic Cycle

The onset of human cytomegalovirus (HCMV) lytic infection is strictly synchronized with the host cell cycle. Infected G0/G1 cells support viral immediate early (IE) gene expression and proceed to the G1/S boundary where they finally arrest. In contrast, S/G2 cells can be infected but effectively block IE gene expression and this inhibition is not relieved until host cells have divided and reentered G1. During latent infection IE gene expression is also inhibited, and for reactivation to occur this block to IE gene expression must be overcome. It is only poorly understood which viral and/or cellular activities maintain the block to cell cycle or latency-associated viral IE gene repression and whether the two mechanisms may be linked. Here, we show that the block to IE gene expression during S and G2 phase can be overcome by both genotoxic stress and chemical inhibitors of cellular DNA replication, pointing to the involvement of checkpoint-dependent signaling pathways in controlling IE gene repression. Checkpoint-dependent rescue of IE expression strictly requires p53 and in the absence of checkpoint activation is mimicked by proteasomal inhibition in a p53 dependent manner. Requirement for the cyclin dependent kinase (CDK) inhibitor p21 downstream of p53 suggests a pivotal role for CDKs in controlling IE gene repression in S/G2 and treatment of S/G2 cells with the CDK inhibitor roscovitine alleviates IE repression independently of p53. Importantly, CDK inhibiton also overcomes the block to IE expression during quiescent infection of NTera2 (NT2) cells. Thus, a timely block to CDK activity not only secures phase specificity of the cell cycle dependent HCMV IE gene expression program, but in addition plays a hitherto unrecognized role in preventing the establishment of a latent-like state

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200–400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of t-tubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart

Behavioural Significance of Cerebellar Modules

A key organisational feature of the cerebellum is its division into a series of cerebellar modules. Each module is defined by its climbing input originating from a well-defined region of the inferior olive, which targets one or more longitudinal zones of Purkinje cells within the cerebellar cortex. In turn, Purkinje cells within each zone project to specific regions of the cerebellar and vestibular nuclei. While much is known about the neuronal wiring of individual cerebellar modules, their behavioural significance remains poorly understood. Here, we briefly review some recent data on the functional role of three different cerebellar modules: the vermal A module, the paravermal C2 module and the lateral D2 module. The available evidence suggests that these modules have some differences in function: the A module is concerned with balance and the postural base for voluntary movements, the C2 module is concerned more with limb control and the D2 module is involved in predicting target motion in visually guided movements. However, these are not likely to be the only functions of these modules and the A and C2 modules are also both concerned with eye and head movements, suggesting that individual cerebellar modules do not necessarily have distinct functions in motor control

Constraints on the structure and seasonal variations of Triton’s atmosphere from the 5 October 2017 stellar occultation and previous observations⋆

Context. A stellar occultation by Neptune's main satellite, Triton, was observed on 5 October 2017 from Europe, North Africa, and the USA. We derived 90 light curves from this event, 42 of which yielded a central flash detection. Aims. We aimed at constraining Triton's atmospheric structure and the seasonal variations of its atmospheric pressure since the Voyager 2 epoch (1989). We also derived the shape of the lower atmosphere from central flash analysis. Methods. We used Abel inversions and direct ray-tracing code to provide the density, pressure, and temperature profiles in the altitude range ∼8 km to ∼190 km, corresponding to pressure levels from 9 μbar down to a few nanobars. Results. (i) A pressure of 1.18 ± 0.03 μbar is found at a reference radius of 1400 km (47 km altitude). (ii) A new analysis of the Voyager 2 radio science occultation shows that this is consistent with an extrapolation of pressure down to the surface pressure obtained in 1989. (iii) A survey of occultations obtained between 1989 and 2017 suggests that an enhancement in surface pressure as reported during the 1990s might be real, but debatable, due to very few high S/N light curves and data accessible for reanalysis. The volatile transport model analysed supports a moderate increase in surface pressure, with a maximum value around 2005-2015 no higher than 23 μbar. The pressures observed in 1995-1997 and 2017 appear mutually inconsistent with the volatile transport model presented here. (iv) The central flash structure does not show evidence of an atmospheric distortion. We find an upper limit of 0.0011 for the apparent oblateness of the atmosphere near the 8 km altitude

The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression

The raw data is available on Mendeley at https://data.mendeley.com/datasets/hfpbctm7tg/draft?a=1c91e494-cadc-4be0-a8ff-91d8736a28e7© The Author(s) 2019. Expression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele.Funding was provided by a Medical Research Council New Investigator Research Grant (MR/P000738/1). Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). D.T., N.S. and D.F. were supported by the EPIGENOMICS FLAGSHIP PROJECT- EPIGEN (project number 08934412) and by University of Insubria. M.T. and S.K. were funded by Ludwig Cancer Research

Promoter methylation of ITF2, but not APC, is associated with microsatellite instability in two populations of colorectal cancer patients

BACKGROUND: Aberrant Wnt signaling activation occurs commonly in colorectal carcinogenesis, leading to upregulation of many target genes. APC (adenomatous polyposis coli) is an important component of the β-catenin destruction complex, which regulates Wnt signaling, and is often mutated in colorectal cancer (CRC). In addition to mutational events, epigenetic changes arise frequently in CRC, specifically, promoter hypermethylation which silences tumor suppressor genes. APC and the Wnt signaling target gene ITF2 (immunoglobulin transcription factor 2) incur hypermethylation in various cancers, however, methylation-dependent regulation of these genes in CRC has not been studied in large, well-characterized patient cohorts. The microsatellite instability (MSI) subtype of CRC, featuring DNA mismatch repair deficiency and often promoter hypermethylation of MutL homolog 1 (MLH1), has a favorable outcome and is characterized by different chemotherapeutic responses than microsatellite stable (MSS) tumors. Other epigenetic events distinguishing these subtypes have not yet been fully elucidated. METHODS: Here, we quantify promoter methylation of ITF2 and APC by MethyLight in two case-case studies nested in population-based CRC cohorts from the Ontario Familial Colorectal Cancer Registry (n = 330) and the Newfoundland Familial Colorectal Cancer Registry (n = 102) comparing MSI status groups. RESULTS: ITF2 and APC methylation are significantly associated with tumor versus normal state (both P < 1.0 × 10(-6)). ITF2 is methylated in 45.8% of MSI cases and 26.9% of MSS cases and is significantly associated with MSI in Ontario (P = 0.002) and Newfoundland (P = 0.005) as well as the MSI-associated feature of MLH1 promoter hypermethylation (P = 6.72 × 10(-4)). APC methylation, although tumor-specific, does not show a significant association with tumor subtype, age, gender, or stage, indicating it is a general tumor-specific CRC biomarker. CONCLUSIONS: This study demonstrates, for the first time, MSI-associated ITF2 methylation, and further reveals the subtype-specific epigenetic events modulating Wnt signaling in CRC