WDR79/TCAB1 plays a conserved role in the control of locomotion and ameliorates phenotypic defects in SMA models

SMN (Survival Motor Neuron) deficiency is the predominant cause of spinal muscular atrophy (SMA), a severe neurodegenerative disorder that can lead to progressive paralysis and death. Although SMN is required in every cell for proper RNA metabolism, the reason why its loss is especially critical in the motor system is still unclear. SMA genetic models have been employed to identify several modifiers that can ameliorate the deficits induced by SMN depletion. Here we focus on WDR79/TCAB1, a protein important for the biogenesis of several RNA species that has been shown to physically interact with SMN in human cells. We show that WDR79 depletion results in locomotion defects in both Drosophila and Caenorhabditis elegans similar to those elicited by SMN depletion. Consistent with this observation, we find that SMN overexpression rescues the WDR79 loss-of-function phenotype in flies. Most importantly, we also found that WDR79 overexpression ameliorates the locomotion defects induced by SMN depletion in both flies and worms. Our results collectively suggest that WDR79 and SMN play evolutionarily conserved cooperative functions in the nervous system and suggest that WDR79/TCAB1 may have the potential to modify SMA pathogenesis

Non-invasive or minimally invasive autopsy compared to conventional autopsy of suspected natural deaths in adults: a systematic review

Objectives: Autopsies are used for healthcare quality control and improving medical knowledge. Because autopsy rates are declining worldwide, various non-invasive or minimally invasive autopsy methods are now being developed. To investigate whether these might replace the invasive autopsies conventionally performed in naturally deceased adults, we systematically reviewed original prospective validation studies. Materials and methods: We searched six databases. Two reviewers independently selected articles and extracted data. Methods and patient groups were too heterogeneous for meaningful meta-analysis of outcomes. Results: Sixteen of 1538 articles met our inclusion criteria. Eight studies used a blinded comparison; ten included less than 30 appropriate cases. Thirteen studies used radiological imaging (seven dealt solely with non-invasive procedures), two thoracoscopy and laparoscopy, and one sampling without imaging. Combining CT and MR was the best non-invasive method (agreement for cause of death: 70 %, 95%CI: 62.6; 76.4), but minimally invasive methods surpassed non-invasive methods. The highest sensitivity for cause of death (90.9 %, 95%CI: 74.5; 97.6, suspected duplicates excluded) was achieved in recent studies combining CT, CT-angiography and biopsies. Conclusion: Minimally invasive autopsies including biopsies performed best. To establish a feasible alternative to conventional autopsy and to increase consent to post-mortem investigations, further research in larger study groups is needed. Key points: • Health care quality control benefits from clinical feedback provided by (alternative) autopsies. • So far, sixteen studies investigated alternative autopsy methods for naturally deceased adults. • Thirteen studies used radiological imaging modalities, eight tissue biopsies, and three CT-angiography. • Combined CT, CT-angiography and biopsies were most sensitive diagnosing cause of death

Inhibitory control, but not prolonged object-related experience appears to affect physical problem-solving performance of pet dogs

Human infants develop an understanding of their physical environment through playful interactions with objects. Similar processes may influence also the performance of non-human animals in physical problem-solving tasks, but to date there is little empirical data to evaluate this hypothesis. In addition or alternatively to prior experiences, inhibitory control has been suggested as a factor underlying the considerable individual differences in performance reported for many species. Here we report a study in which we manipulated the extent of object-related experience for a cohort of dogs (Canis familiaris) of the breed Border Collie over a period of 18 months, and assessed their level of inhibitory control, prior to testing them in a series of four physical problem-solving tasks. We found no evidence that differences in object-related experience explain variability in performance in these tasks. It thus appears that dogs do not transfer knowledge about physical rules from one physical problem-solving task to another, but rather approach each task as a novel problem. Our results, however, suggest that individual performance in these tasks is influenced in a complex way by the subject’s level of inhibitory control. Depending on the task, inhibitory control had a positive or a negative effect on performance and different aspects of inhibitory control turned out to be the best predictors of individual performance in the different tasks. Therefore, studying the interplay between inhibitory control and problem-solving performance will make an important contribution to our understanding of individual and species differences in physical problem-solving performance

Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation

Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.Lewis Katz School of MedicineCancer and Cellular Biolog

Partitioning of sediment on the shelf offshore of the Columbia River littoral cell

This paper is not subject to U.S. copyright. The definitive version was published in Marine Geology 273 (2010): 11-31, doi:10.1016/j.margeo.2010.02.001.Sediment derived from the Columbia River has been deposited on the continental shelf, along the barriers and beaches, and in the bays of the Oregon and Washington coast during the Holocene. The barrier and beach deposits of this 150-km section of coast comprise approximately 6 km3 of these Holocene sediments (Peterson et al., 2010-this issue) while the fluvial and bay deposits comprise about 104 km3 (Baker et al., 2010-this issue), and the shelf deposit is approximately 79 km3. Seismic-reflection, sidescan sonar, and surface sediment data show that the shelf deposit is not uniform in distribution or composition. The shelf deposit is 15–50 m thick off the beaches of the southern part of the study area but is less than 3 m thick, and, in places, absent from the inner shelf in the northern third of the study area. Surface sediment texture of the shelf deposit varies as well. Pleistocene-age gravel covers parts of the inner shelf in the northern third of the area. To the south, the surface of the Holocene shelf deposit is composed of fine sand near shore that grades offshore to dominantly very fine sand in 25–30 m water depth and muddy sand on the middle and outer shelf (> 50 m depth). Although a huge volume of sediment covers the shelf, its uneven distribution indicates that in places only small amounts are available as a potential offshore source to the adjacent beaches, and in other places the finer-grained nature of the shelf deposit indicates that significant winnowing of fine sediment would be necessary to make it compositionally equivalent to sediment on adjacent beaches

Vemurafenib treatment of pleomorphic xanthoastrocytoma in a child with Down syndrome

Brain tumors are the most common solid neoplasms of childhood, but they are very rarely reported in children with Down Syndrome (DS), who develop more commonly different types of malignancies. In particular, we hereby report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. Brain imaging revealed the presence of a mass that was partially resected revealing a histological diagnosis of Pleomorphic Xanthoastrocytoma (PXA), a rare WHO grade II tumor extending from the diencephalic region into the surrounding brain tissue. These tumors can harbor the BRAF mutation p.V600E, targetable by the specific inhibitor Vemurafenib. After confirming the presence of the mutation in the tumor, the patient was treated with Vemurafenib. The treatment proved to be effective, leading to a partial response and a stabilization of the disease. Usually, in patients with DS a reduction of the dose of chemotherapeutic drugs is necessary. Vemurafenib was instead well-tolerated as the only observed adverse effect was grade I skin toxicity. This is, to our knowledge, the first case of a PXA reported in a child with DS and the first DS patient treated with Vemurafenib

The S-adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening

Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S-adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels.Lewis Katz School of MedicineCancer and Cellular Biolog

Investigating the Performance of a Degraded Prestressed Concrete Box Girder Half-joint Bridge in the Spirit of the Italian Guidelines

The paper investigates a paired pre-stressed box-girder concrete bridge, according to the framework suggested by the new Italian Guidelines for the risk assessment of existing bridges. The bridges, selected as case study within the research agreement signed by the FABRE Consortium and ANAS S.p.A. for first applications of the Italian Guidelines, present significant age-related degradation phenomena known to the Administrator, who decided for the bridges demolition and reconstruction. Visual inspections confirmed defects in the pre-stressing system, a permanent deflection of the deck, and cracks at half-joints, possibly due to pre-stressing loss and creep effects triggered by the poor quality of concrete. Also, preliminary safety verifications revealed not to meet code requirements in most cross-sections. Consequently, the most degraded bridge was closed. From March 2022, experimental campaigns have been performed by the FABRE Consortium and ANAS for improving their experience on the behaviour of old pre-stressed concrete bridges, as well as to control possible performance loss of the open bridge, sustaining the overall route traffic. The paper summarises these activities and presents some possible future investigations to be carried out before bridge demolition

Oligonucleotide IMT504 induces an immunogenic phenotype and apoptosis in chronic lymphocytic leukemia cells

Oligonucleotides (ODNs) of the PyNTTTTGT class directly stimulate B lymphocytes and plasmacytoid dendritic cells of the immune system of primates. Here we investigated the ability of the PyNTTTTGT ODN prototype IMT504 to regulate the expression of surface molecules and apoptosis in human B-chronic lymphocytic leukemia (CLL) cells. The surface molecules CD25, CD40, CD80 and CD86 were up-regulated upon incubation of the B-CLL cells with IMT504. Co-stimulation with IL-2 resulted in further up-regulation. IMT504-activated B-CLL cells were also good stimulators of T cells in allogeneic mixed lymphocyte reactions and co-stimulation with IL-2 improved this stimulation capacity. Apoptosis of the B-CLL cells in vitro was also stimulated by incubation with IMT504. In this case, co-stimulation with IL-2 was not significant. Furthermore, B-CLL cells of all the patients studied developed an immunogenic phenotype and entered stimulated apoptosis upon in vitro incubation with IMT504 independently of the mutational status of their 1gVH genes, becoming a good marker for tumor progression.Fil:Elias, F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina