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Protein domains without the usual distribution of amino acids, called low complexity (LC) domains, can be prone to self-assembly into amyloid-like fibrils. Self-assembly of LC domains that are nearly devoid of hydrophobic residues, such as the 214-residue LC domain of the RNA-binding protein FUS, is particularly intriguing from the biophysical perspective and is biomedically relevant due to its occurrence within neurons in amyotrophic lateral sclerosis, frontotemporal dementia, and other neurodegenerative diseases. We report a high-resolution molecular structural model for fibrils formed by the C-terminal half of the FUS LC domain (FUS-LC-C, residues 111-214), based on a density map with 2.62 Å resolution from cryo-electron microscopy (cryo-EM). In the FUS-LC-C fibril core, residues 112-150 adopt U-shaped conformations and form two subunits with in-register, parallel cross-β structures, arranged with quasi-2 1 symmetry. All-atom molecular dynamics simulations indicate that the FUS-LC-C fibril core is stabilized by a plethora of hydrogen bonds involving sidechains of Gln, Asn, Ser, and Tyr residues, both along and transverse to the fibril growth direction, including diverse sidechain-to-backbone, sidechain-to-sidechain, and sidechain-to-water interactions. Nuclear magnetic resonance measurements additionally show that portions of disordered residues 151-214 remain highly dynamic in FUS-LC-C fibrils and that fibrils formed by the N-terminal half of the FUS LC domain (FUS-LC-N, residues 2-108) have the same core structure as fibrils formed by the full-length LC domain. These results contribute to our understanding of the molecular structural basis for amyloid formation by FUS and by LC domains in general. The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.

Using the hard-sphere model with the existing tabulated values of ionic radii to calculate the lattice parameters of minerals does not always match experimental data. An adaptation of this crystallographic model is proposed by considering the cations and anions as hard and soft close-packed spheres, respectively. We demonstrate the relevance of this “hybrid model” by combining Pauling’s first rule with experimental unit-cell parameters of fluorite and antifluorite-structured systems to revise the ionic radii of their constitutive species.

Germ granules are non-membranous ribonucleoprotein granules deemed the hubs for post-transcriptional gene regulation and functionally linked to germ cell fate across species. Little is known about the physical properties of germ granules and how these relate to germ cell function. Here we study two types of germ granules in the Drosophila embryo: cytoplasmic germ granules that instruct primordial germ cells (PGCs) formation and nuclear germ granules within early PGCs with unknown function. We show that cytoplasmic and nuclear germ granules are phase transitioned condensates nucleated by Oskar protein that display liquid as well as hydrogel-like properties. Focusing on nuclear granules, we find that Oskar drives their formation in heterologous cell systems. Multiple, independent Oskar protein domains synergize to promote granule phase separation. Deletion of Oskar’s nuclear localization sequence specifically ablates nuclear granules in cell systems. In the embryo, nuclear germ granules promote germ cell divisions thereby increasing PGC number for the next generation.

Human genetic studies have given evidence of familial, disease-causing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in disease-causing conformations.

Background and objectives Hepatic resection is established as the treatment for HCC. However, patients sometimes experience early recurrence of HCC (ER HCC) after curative resection. Methods A retrospective analysis was conducted for 193 patients with single HCC who underwent curative liver resection in our medical center between April 2000 and March 2013. We divided the cohort into two groups; early recurrence group (ER G) which experienced recurrence within 6 months after resection, and non-early recurrence group (NER G). Risk factors for ER HCC were analyzed. Results Thirty-nine out of 193 (20.2 %) patients had ER HCC. Univariate analysis showed Glasgow prognostic score (GPS, p  = 0.036), neutrophil to lymphocyte ratio (NLR, p  = 0.001), level of PIVKA-II ( p  = 0.0001), level of AFP ( p  = 0.0001), amounts of blood loss ( p  = 0.001), operating time ( p  = 0.002), tumor size ( p  = 0.0001), stage III and IV ( p  = 0.0001), and microvascular invasions (portal vein: p  = 0.0001 and hepatic vein: p  = 0.001) to be associated with ER HCC. By multivariate analysis, there were significant differences in high NLR ( p  = 0.029) and high AFP ( p  = 0.0001) in patients with ER HCC. Conclusions Preoperative high AFP (more than 250 ng/ml) and high NLR (more than 1.829) were independent risk factors for ER HCC.

In recent years, a novel technique has been employed to maintain a distance between the prostate and the rectum by transperineally injecting a hydrogel spacer (HS). However, the effect of HS on the prostate positional displacement is poorly understood, despite its stability with HS in place. In this study, we investigated the effect of HS insertion on the interfraction prostate motion during the course of proton therapy (PT) for Japanese prostate cancer patients. The study population consisted of 22 cases of intermediate-risk prostate cancer with 11 cases with HS insertion and 11 cases without HS insertion. The irradiation position and preparation were similar for both groups. To test for reproducibility, regular confirmation computed tomography (RCCT) was done four times during the treatment period, and five times overall [including treatment planning CT (TPCT)] in each patient. Considering the prostate position of the TPCT as the reference, the change in the center of gravity of the prostate relative to the bony anatomy in the RCCTs of each patient was determined in the left–right (LR), superior–inferior (SI) and anterior–posterior (AP) directions. As a result, no significant difference was observed across the groups in the LR and SI directions. Conversely, a significant difference was observed in the AP direction (P < 0.05). The proportion of the 3D vector length ≤5 mm was 95% in the inserted group, but 55% in the non-inserted group. Therefore, HS is not only effective in reducing rectal dose, but may also contribute to the positional reproducibility of the prostate.

Purpose: To quantitatively evaluate how much the doses to organs at risk are affected in the prone position compared to the supine position in the proton therapy (PT) for prostate cancer. Materials and Methods: Fifteen consecutive patients with clinically localized prostate cancer underwent treatment planning computed tomography scans in both the supine and prone positions. The clinical target volume (CTV) consisted of the prostate gland plus the seminal vesicles. The PT plans were designed using the standard lateral opposed fields with passively scattered proton beams for both treatment positions. The prescribed dose for each plan was set to 78 Gy (Relative biological effectiveness)/39 fractions to 50% of the planning target volume. Dose-volume metrics of the rectum and bladder in the two treatment positions were analyzed. Results: It was confirmed that all the parameters of D05, D10, D20, D30, Dmean, and V90 examined in the rectum were significantly reduced in the prone position. There was no significant difference between the two positions in the bladder dose except for Dmean. The distance between the CTV and the rectum tended to increase with the patient in the prone position; at the prostate level, however, the maximum change was approximately 5 mm, and there was significant variation between cases. Conclusions: We confirmed that the rectal doses were significantly lower in the prone compared with the supine position in PT. Although uncertain, the prone position could be an effective method to reduce the rectal dose in PT.

Few studies have investigated the Glasgow Prognostic Score (GPS) in patients with hepatocellular carcinoma (HCC). This study compared the prognostic value of the GPS and Cancer of the Liver Italian Program (CLIP) score in patients undergoing surgery for HCC. A total of 398 patients were evaluated retrospectively. Kaplan–Meier analyses revealed that GPS ( P < .001) and CLIP score ( P < .001) were associated with overall survival. GPS could classify patients with low CLIP score (0 or 1) into 3 independent groups ( P < .001). Univariate analyses selected GPS ( P = .006) and CLIP score ( P = .002) as the predictive factors associated with overall survival. Multivariate analysis using these 2 scoring systems disclosed that both GPS ( P = .025) and CLIP score ( P = .010) were associated with overall survival. GPS is not only an important predictor of overall survival after surgical treatment of HCC as well as CLIP score, but also is able to clearly divide patients with low CLIP score into 3 independent groups.

The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion ( P =0.004), lymph node metastasis ( P <0.001), and advanced stage ( P =0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression ( P =0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.