Structural Basis of Impaired Disaggregase Function in the Oxidation-sensitive Skd3 Mutant Causing 3-methylglutaconic Aciduria

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD

Novel management of expected post-radiotherapy complications in hepatocellular carcinoma patients: a case report

In recent years, radiotherapy (RT) has been used to treat hepatocellular carcinoma (HCC) at each stage. This clinical trend has developed with the increasing improvement of RT techniques, which show clinical results comparable to those of other treatment modalities. Intensity-modulated radiotherapy uses a high radiation dose to improve treatment effectiveness. However, the associated radiation toxicity can damage adjacent organs. Radiation-induced gastric damage with gastric ulcers is a complication of RT. This report presents a novel management strategy for preventing post-RT gastric ulcers. We present the case of a 53-year-old male patient diagnosed with HCC, who experienced gastric ulcer after RT. Before the second round of RT, the patient was administered a gas-foaming agent, which was effective in preventing RT complications

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Molecular chaperones: guardians of the proteome in normal and disease states [version 1; referees: 2 approved]

Proteins must adopt a defined three-dimensional structure in order to gain functional activity, or must they? An ever-increasing number of intrinsically disordered proteins and amyloid-forming polypeptides challenge this dogma. While molecular chaperones and proteases are traditionally associated with protein quality control inside the cell, it is now apparent that molecular chaperones not only promote protein folding in the “forward” direction by facilitating folding and preventing misfolding and aggregation, but also facilitate protein unfolding and even disaggregation resulting in the recovery of functional protein from aggregates. Here, we review our current understanding of ATP-dependent molecular chaperones that harness the energy of ATP binding and hydrolysis to fuel their chaperone functions. An emerging theme is that most of these chaperones do not work alone, but instead function together with other chaperone systems to maintain the proteome. Hence, molecular chaperones are the major component of the proteostasis network that guards and protects the proteome from damage. Furthermore, while a decline of this network is detrimental to cell and organismal health, a controlled perturbation of the proteostasis network may offer new therapeutic avenues against human diseases

Cryo-EM Structures of the Hsp104 Protein Disaggregase Captured in the ATP Conformation

Hsp104 is a ring-forming, ATP-driven molecular machine that recovers functional protein from both stress-denatured and amyloid-forming aggregates. Although Hsp104 shares a common architecture with Clp/Hsp100 protein unfoldases, different and seemingly conflicting 3D structures have been reported. Examining the structure of Hsp104 poses considerable challenges because Hsp104 readily hydrolyzes ATP, whereas ATP analogs can be slowly turned over and are often contaminated with other nucleotide species. Here, we present the single-particle electron cryo-microscopy (cryo-EM) structures of a catalytically inactive Hsp104 variant (Hsp104(DWB)) in the ATP-bound state determined between 7.7 angstrom and 9.3 angstrom resolution. Surprisingly, we observe that the Hsp104DWB hexamer adopts distinct ring conformations (closed, extended, and open) despite being in the same nucleotide state. The latter underscores the structural plasticity of Hsp104 in solution, with different conformations stabilized by nucleotide binding. Our findings suggest that, in addition to ATP hydrolysis-driven conformational changes, Hsp104 uses stochastic motions to translocate unfolded polypeptides.Y

Prognostic value of integrated cytogenetic, somatic variation, and copy number variation analyses in Korean patients with newly diagnosed multiple myeloma.

BackgroundTo investigate the prognostic value of gene variants and copy number variations (CNVs) in patients with newly diagnosed multiple myeloma (NDMM), an integrative genomic analysis was performed.MethodsSixty-seven patients with NDMM exhibiting more than 60% plasma cells in the bone marrow aspirate were enrolled in the study. Whole-exome sequencing was conducted on bone marrow nucleated cells. Mutation and CNV analyses were performed using the CNVkit and Nexus Copy Number software. In addition, karyotype and fluorescent in situ hybridization were utilized for the integrated analysis.ResultsEighty-three driver gene mutations were detected in 63 patients with NDMM. The median number of mutations per patient was 2.0 (95% confidence interval [CI] = 2.0-3.0, range = 0-8). MAML2 and BHLHE41 mutations were associated with decreased survival. CNVs were detected in 56 patients (72.7%; 56/67). The median number of CNVs per patient was 6.0 (95% CI = 5.7-7.0; range = 0-16). Among the CNVs, 1q gain, 6p gain, 6q loss, 8p loss, and 13q loss were associated with decreased survival. Additionally, 1q gain and 6p gain were independent adverse prognostic factors. Increased numbers of CNVs and driver gene mutations were associated with poor clinical outcomes. Cluster analysis revealed that patients with the highest number of driver mutations along with 1q gain, 6p gain, and 13q loss exhibited the poorest prognosis.ConclusionsIn addition to the known prognostic factors, the integrated analysis of genetic variations and CNVs could contribute to prognostic stratification of patients with NDMM

“Non-equilibrium” grain boundaries in additively manufactured CoCrFeMnNi high-entropy alloy: Enhanced diffusion and strong segregation

International audienceGrain boundary diffusion in an additively manufactured equiatomic CoCrFeMnNi high-entropy alloy is systematically investigated at 500 K under the so-called C-type kinetic conditions when bulk diffusion is completely frozen. In the as-manufactured state, general (random) grain boundaries are found to be characterized by orders-of-magnitude enhanced diffusivities and a non-equilibrium segregation of (dominantly) Mn atoms. These features are explained in terms of a non-equilibrium state of grain boundaries after rapid solidification. The grain boundary diffusion rates are found to be almost independent on the scanning/building strategy used for the specimen’s manufacturing, despite pronounced microstructure differences. Grain boundary migration during diffusion annealing turned out to preserve the non-equilibrium state of the interfaces due to continuous consumption of the processing-induced defects by moving boundaries. Whereas the kinetic “non-equilibrium” state of the interfaces relaxes after annealing at 773 K, the non-equilibrium segregation is retained, being further accompanied by a nano-scale phase decomposition at the grain boundaries. The generality of the findings for additively manufactured materials is discussed

Reduced Graphene Oxide/LiI Composite Lithium Ion Battery Cathodes

Li-iodine chemistry is of interest for electrochemical energy storage because it has been shown to provide both high power and high energy density. However, Li-iodine batteries are typically formed using Li metal and elemental iodine, which presents safety and fabrication challenges (e.g., the high vapor pressure of iodine). These disadvantages could be circumvented by using LiI as a starting cathode. Here, we present fabrication of a reduced graphene oxide (rGO)/LiI composite cathode, enabling for the first time the use of LiI as the Li-ion battery cathode. LiI was coated on rGO by infiltration of an ethanolic solution of LiI into a compressed rGO aerogel followed by drying. The free-standing rGO/LiI electrodes show stable long-term cycling and good rate performance with high specific capacity (200 mAh g^–1 at 0.5 C after 100 cycles) and small hysteresis (0.056 V at 1 C). Shuttling was suppressed significantly. We speculate the improved electrochemical performance is due to strong interactions between the active materials and rGO, and the reduced ion and electron transport distances provided by the three-dimensional structured cathode