Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation.     

Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma

Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.Subject terms: Nuclear organization, Cancer     

Prevalence rate and risk factors of human cystic echinococcosis: A cross-sectional,community-based,abdominal ultrasound study in rural and urban north-central Chile

BackgroundCystic echinococcosis (CE) caused by Echinococcus granulosus sensu lato (s.l.) is a neglected and underdiagnosed parasitic zoonosis that has a significant socioeconomic impact on rural communities relying on livestock farming. CE is endemic across Latin America, including Chile, where the Coquimbo region exhibits a relatively high record of hospital-based human cases and infected animals. However, the incidence of hospitalized CE cases may underestimate the real burden of infection in a population, since the majority of cases never reach medical attention or official disease records.Methodology/Principal findingsIn 2019, a cross-sectional, community-based study was conducted with the objectives of estimating for the first time the prevalence of human abdominal CE using abdominal ultrasound (US) screening in volunteers residing in urban and rural localities of the Monte Patria municipality located in Limarí province, Coquimbo region, Chile, and identifying the risk factors associated with human infection. Pre-screening activities included a 16-h lecture/hands-on training aimed at rural physicians that focused on the diagnosis of CE by US, based on current WHO recommendations. A total of 2,439 (~8% of municipality inhabitants) people from thirteen target localities were screened by abdominal US in June-July 2019. We found an overall CE prevalence of 1.6% (95% CI 1.1–2.2) with a significantly higher likelihood of infection in rural localities, older age classes and people drinking non-potable water; 84.6% of infected volunteers were newly diagnosed with CE. Cysts were either in active or inactive stages in equal proportions; active cysts were detected in all age classes, while 95.7% of inactive cysts occurred in >40 years-old subjects.Conclusions/SignificanceThis is the first US survey aimed at detecting human infection caused by Echinococcus granulosus s.l. in Chile. Our findings indicate a high CE prevalence in the area, and contribute to define the demographic and behavioral risk factors promoting the transmission of the parasitic infection within target communities. Our results support the implementation of cost-effective strategies for the diagnosis, treatment and control of CE, and the need to improve the epidemiological surveillance system in Chile.     

Effect of different growth hormone dosages on the growth velocity in children born small for gestational age

To assess whether short-term growth hormone (GH) treatment can improve the linear growth in children who were born small for gestational age (SGA), we started a randomized multicenter trial in 26 age- and sex-matched prepubertal children born SGA. During the 1st year of GH therapy, all children received GH 0.23 mg/kg/week, then during the 2nd year, 13 children received the same dose (group A), and in the other 13 children, the dose of GH was doubled, i.e., 0.46 mg/kg/week (group B). During the 1st year of therapy, the growth velocity significantly (p<0.0001) increased in all patients. During the 2nd year, group A showed a significant decrease of the growth velocity (p<0.015), whereas group B maintained the growth rate. The height in group A children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000002 and p<0.000001, respectively), reaching the normal range in 8 out of 13 children at the end of 2 years of GH therapy. The height in group B children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000001 and p<0.000001, respectively), reaching the normal range in all 11 children who completed the GH therapy. The height gain was similar in groups A and B treated with the same GH dosage during the 1st year of therapy. A greater increase in height gain was found in children of group B treated with the higher GH dosage during the 2nd year of therapy as compared with group A (p<0.02). Significant increases in insulin-like growth factor I (p<0.0001), acid-labile subunit (p<0.0002), and bone/chronological age ratio (p<0.0001) were found after the 1st year of GH therapy, but no significant changes were observed during the 2nd year, independently of the GH dose. In conclusion, the height velocity of children born SGA significantly increases during the 1st year of GH therapy, diminishes, but can decrease during the 2nd year, if the GH dosage is not raised.     

A model of chromosome aberration induction and chronic myeloid leukaemia incidence at low doses

Some chromosome aberration types, generally translocations, are correlated with specific cancers. An example is provided by chronic myeloid leukemia (CML) cells, most of which carry a translocation involving the ABL gene on chromosome 9 and the BCR gene on chromosome 22. The hypothesis of a causal relationship between CML and the chimeric protein product of the BCR-ABL translocation has recently received strong support. In this framework, a mechanistic model and Monte-Carlo code simulating radiation-induced chromosome aberrations in human lymphocytes will be presented. The current version of the model can predict dose-response curves for the main aberration types following acute irradiation with gamma rays and light ions of different energies. The model is based on the assumption that only clustered DNA lesions can lead to aberrations and that only lesion free ends in neighbouring chromosome territories can join and form exchanges. Such lesions are distributed within the cell nucleus according to the radiation track structure, i.e. randomly for low-LET radiation and along straight lines for high-LET light ions. Interphase chromosome territories are explicitly simulated and background aberrations are taken into account. Very good agreement was found with experimental data taken from the literature that provided a further validation of the model. As an application, yields of BCR-ABL translocations were calculated. Preliminary results led to a CML induction dose-response that is approximately quadratic below 0.1 Gy and essentially linear at higher doses up to 1 Gy. The numerical values obtained for the probability of CML induction are consistent with values obtained by other groups with different approaches.Dedicated to Herwig Paretzke on the occasion of his 60th birthday.     

Molecular mechanisms in prostate cancer. A review

Genetic studies have provided remarkable clues to the causes of prostate cancer (PCa). For example, in addition to the expected role of androgens in facilitating the development of PCa, the possibility that infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate cancer genes; that insight will profoundly affect future studies and may ultimately lead to new approaches to the prevention of prostate cancer. The identification of key molecular alterations in prostate cancer cells implicates carcinogen defenses, including GSTP1, growth factor signaling pathways (such as NKX3.1, PTEN and p27) and androgens as critical determinants of the phenotype of PCa cells and defines specific targets for detection, diagnosis and treatment of PCa.