The role of Aspergillus nidulans polo-like kinase PlkA in microtubule-organizing center control.

Centrosomes are important microtubule-organizing centers (MTOC) in animal cells. In addition, non-centrosomal MTOCs (ncMTOCs) have been described in many cell types. The functional analogs of centrosomes in fungi are the spindle pole bodies (SPBs). In Aspergillus nidulans, additional MTOCs have been discovered at septa (sMTOC). Although the core components are conserved in both MTOCs, their composition and organization are different and dynamic. Here, we show that the polo-like kinase PlkA binds the γ-tubulin ring complex (γ-TuRC) receptor protein ApsB and contributes to targeting ApsB to both MTOCs. PlkA coordinates the activities of the SPB outer plaque and the sMTOC. PlkA kinase activity was required for astral MT formation involving ApsB recruitment. PlkA also interacted with the γ-TuRC inner plaque receptor protein PcpA. Mitosis was delayed without PlkA, and the PlkA protein was required for proper mitotic spindle morphology, although this function was independent of its catalytic activity. Our results suggest that the polo-like kinase is a regulator of MTOC activities and acts as a scaffolding unit through interaction with γ-TuRC receptors.

Internal reuse of methanol-to-olefin wastewater based on micro-channel separation coupling hydrocyclone regeneration.

Methanol-to-olefin (MTO) is a typical new coal chemical industry example. Due to the large volume of generated wastewater, complex composition including catalysts, aromatics and various oxygen-containing compounds, and serious environmental hazard, wastewater recycling is critical for sustainable industrial development and ecological protection. Herein, a swirl regenerating micro-channel separation (SRMS) technology was proposed to integrate deep filtration and hydrocyclone-enhanced regeneration. A small-scale experimental investigation was first conducted to verify the feasibility of the MTO wastewater treatment. A pilot SRMS device with a treatment capacity of 20 m3/h was constructed, and the device's continuous operation effect and stability were comprehensively evaluated. The separation performance of the SRMS device at different solution pH values and the impact of the hydrocyclone-enhanced regeneration of separation media were discussed in detail. At low solution pH values (<7), the SRMS device exhibits an average separation efficiency of 92.0% for fine particulate matter in wastewater, and the median particle size, d50, decreases from 1.55 to 0.6 µm. As the solution pH increases, the repulsive energy barrier for the medium-contaminant and contaminant-contaminant increases, inhibiting the deposition behavior of particulate pollutants. In addition, hydrocyclone desorbs contaminants deposited on the separation media and the average contaminant residual rate decreases from 3.3 to 0.2 wt%. We propose an industrial application for treating and reusing MTO wastewater (200 m3/h) using the SRMS technology based on the experimental results. The costs of the wastewater treatment process are as low as 0.25 CNY/m3, and the wastewater reuse rate is over 97% without chemical consumption. This work can provide an environmentally friendly and economically sustainable approach to the source management of MTO wastewater.

Influence of ZSM-5 Crystal Size on Methanol-to-Olefin (MTO) vs. Ethanol-to-Aromatics (ETA) Conversion.

Crystal size is a key parameter of zeolites applied as catalysts. Herein, ZSM-5 crystals with similar physicochemical and acid properties, few defects, and aluminum exclusively in tetrahedral coordination are synthesized and the influence of the crystal size on the MTO and ETA conversion is investigated. Short olefins are the main products of the MTO conversion, whereas larger olefins and aromatics dominate the products after ETA conversion. In the case of both feeds, an increased crystal size decreases the catalyst's lifetime. The MTO conversion over larger ZSM-5 altered the product distribution, which was not the case for the ETA conversion. The reason is that the instantly available aromatics during ETA conversion lead to fast coking and zeolite crystals only active in the outer layers. Thus, the different reactivity of different-sized ZSM-5 is direct proof of a different conversion mechanism for both alcohols.

Reconstructing electron transfer components from an Fe(II) oxidizing bacterium.

Neutrophilic Fe(II) oxidizing bacteria play an important role in biogeochemical processes and have also received attention for multiple technological applications. These micro-organisms are thought to couple their metabolism with extracellular electron transfer (EET) while oxidizing Fe(II) as electron donor outside the cell. Sideroxydans lithotrophicus ES-1 is a freshwater chemolithoautotrophic Fe(II) oxidizing bacterium that is challenging to culture and not yet genetically tractable. Analysis of the S. lithotrophicus ES-1 genome predicts multiple EET pathways, which are proposed to be involved in Fe(II) oxidation, but not yet validated. Here we expressed components of two of the proposed EET pathways, including the Mto and Slit_0867-0870 PCC3 pathways, from S. lithotrophicus ES-1 into Aeromonas hydrophila, an established model EET organism. We demonstrate that combinations of putative inner membrane and periplasmic components from the Mto and Slit_0867-0870 PCC3 pathways partially complemented EET activity in Aeromonas mutants lacking native components. Our results provide evidence for electron transfer functionality and interactions of inner membrane and periplasmic components from the Mto and Slit_0867-0870 PCC3 pathways. Based on these findings, we suggest that EET in S. lithotrophicus ES-1 could be more complicated than previously considered and raises questions regarding directionality of these electron transfer pathways.

Synthesis and Applications of SAPO-34 Molecular Sieves.

Silicoaluminophosphate zeolite (SAPO-34) has been attracting increasing attention due to its excellent form selection and controllability in the chemical industry, as well as being one of the best industrial catalysts for methanol-to-olefin (MTO) reaction conversion. However, as a microporous molecular sieve, SAPO-34 easily generates carbon deposition and rapidly becomes inactivated. Therefore, it is necessary to reduce the crystal size of the zeolite or to introduce secondary macropores into the zeolite crystal to form a hierarchical structure in order to improve the catalytic effect. In this review, the synthesis methods of conventional SAPO-34 molecular sieves, hierarchical SAPO-34 molecular sieves and nanosized SAPO-34 molecular sieves are introduced, and the properties of the synthesized SAPO-34 molecular sieves are described, including the phase, morphology, pore structure, acid source, and catalytic performance, in particular with respect to the synthesis of hierarchical SAPO-34 molecular sieves. We hope that the review can provide guidance to the preparation of the SAPO-34 catalysts, and stimulate the future development of high-performance hierarchical SAPO-34 catalysts to meet the growing demands of the material and chemical industries.

Circular RNA mitochondrial translation optimization 1 correlates with less lymph node metastasis, longer disease-free survival, and higher chemotherapy sensitivity in gastric cancer.

OBJECTIVE: Circular-mitochondrial translation optimization 1 (circ-MTO1) inhibits the progression of gastric cancer by regulating the growth, apoptosis, and invasion of tumor cells. However, its clinical potential as a biomarker for gastric cancer remains to be further evaluated. This study aimed to assess circ-MTO1 expression and its correlation with clinical features and prognosis in gastric cancer patients, as well as the effect of circ-MTO1 on the sensitivity to chemotherapy in gastric cancer cells. METHODS: Circ-MTO1 in tumor and adjacent tissues of 97 gastric cancer patients undergoing resection was examined by reverse transcription-quantitative polymerase chain reaction. HGC-27 and NCI-N87 cells transfected by circ-MOT1 overexpression plasmid (OE-circ-MOT1) and negative control (OE-NC) were treated with 0-6.4 µM oxaliplatin. Relative cell viability was detected using Cell Counting Kit-8. RESULTS: Circ-MTO1 was insufficiently expressed in gastric tumor tissue (median (interquartile range): 0.403 (0.288-0.518)) compared with adjacent tissue (median (interquartile range): 1.000 (0.715-1.524)) (p < 0.001). Besides, tumor circ-MTO1 was correlated with less lymph node metastasis (p = 0.014) and low TNM stage (p = 0.039), while was not correlated with demographic features or other clinical characteristics (all p > 0.05). Furthermore, tumor circ-MTO1 high expression was independently correlated with prolonged disease-free survival (DFS) (p = 0.013, adjusted hazard ratio (95% confidential interval): 0.314 (0.126-0.782)), but was not correlated with overall survival (p > 0.05). Lastly, in gastric cancer cells, OE-circ-MTO1 apparently decreased relative cell viabilities at oxaliplatin concentrations of 0.4, 0.8, 1.6, and 3.2 µM (all p < 0.05). CONCLUSION: Circ-MTO1 correlates with less lymph node metastasis, prolonged DFS, and improved chemotherapy sensitivity in gastric cancer.

Combined Ex and In Situ Measurements Elucidate the Dynamics of Retained Species in ZSM-5 and SAPO-18 Catalysts Used in the Methanol-to-Olefins Reaction.

The dynamics of the retained species on ZSM-5 and SAPO-18 catalysts are studied by using a combination of temperature-programmed desorption/oxidation, ex situ analysis, and in situ FTIR spectroscopic measurements over the entire conversion range, using fixed-bed and spectroscopic cell reactors, in continuous and discontinuous mode. The results point to the appropriateness of the combined methodologies to track the interconversion of active into deactivating species. A statistically relevant (supported by linear regression and multivariate analysis) association of the observations is found by using the different complementary methodologies. The kinetics of this interconversion depends on the initial conversion (tuned by acidity and space time) and microporous topology, and involve: (i) in the ZSM-5 catalysts, the diffusion of monocyclic aromatics toward the exterior of the zeolite to form coke, and (ii) in the SAPO-18 catalysts, the obstruction of the cavities by aromatics that grow into tetracyclic aromatic islands.

Circular RNA MTO1 intercorrelates with microRNA-630, both associate with Enneking stage and/or pathological fracture as well as prognosis in osteosarcoma patients.

OBJECTIVE: Circular RNA-mitochondrial tRNA translation optimization 1 (circ-MTO1) not only involves in bioprocess of various cancers, but also regulates osteosarcoma progression by regulating microRNA-630 (miR-630). However, the clinical role of circ-MTO1 and miR-630 in osteosarcoma is still obscure. This study aimed to assess the correlation of circ-MTO1 and miR-630 with disease features and prognosis and to explore their association with each other in osteosarcoma patients. METHODS: Forty-four osteosarcoma patients who received neoadjuvant chemotherapy to surgical resection were analyzed in this retrospective study. Then, circ-MTO1 and miR-630 expressions were evaluated in tumor and adjacent non-tumor specimens by reverse transcription quantitative polymerase chain reaction. RESULTS: Circ-MTO1 was lower in tumor than in non-tumor tissues (p<0.001); meanwhile, its elevated tumor expression was correlated with less advanced Enneking stage (p=0.049), good neoadjuvant chemotherapy response (p=0.029), and longer disease-free survival (DFS) (p=0.047). However, no association was found between circ-MTO1 and overall survival (OS) (p=0.122). Additionally, miR-630 in tumor was higher than in non-tumor tissues (p<0.001), while its raised tumor expression was associated with pathological fracture occurrence (p=0.003), advanced Enneking stage (p=0.036), poor neoadjuvant chemotherapy response (p=0.035), and shorter DFS (p=0.011). However, no association was found between miR-630 and OS (p=0.066). In addition, tumor circ-MTO1 was negatively associated with miR-630 (r=-0.323, p=0.032). CONCLUSION: Circ-MTO1 and miR-630 expressions are inter-correlated and dysregulated in osteosarcoma patients. Besides, they associate with Enneking stage and/or pathological fracture, as well as neoadjuvant treatment response and accumulating DFS in these patients.

Errors linked to medication management in nursing homes: an interview study.

BACKGROUND: The number of errors in medication management in nursing homes is increasing, which may lead to potentially life-threatening harm. Few studies on this subject are found in the municipal nursing home setting, and causes need to be identified. The aim of this study was to explore perceptions of errors connected to medication management in nursing homes by exploring the perspective of first-line registered nurses, registered nurses, and non-licensed staff involved in the care of older persons. METHODS: A qualitative research approach was applied based on semi-structured interviews with 21 participants at their workplaces: Seven in each of the occupational categories of first-line registered nurses, registered nurses, and non-licensed staff. Subcategories were derived from transcribed interviews by content analysis and categorized according to the Man, Technology, and Organization concept of error causation, which is as a framework to identify errors. RESULTS: Mistakes in medication management were commonly perceived as a result of human shortcomings and deficiencies in working conditions such as the lack of safe tools to facilitate and secure medication management. The delegation of drug administration to non-licensed staff, the abandonment of routines, carelessness, a lack of knowledge, inadequate verbal communication between colleagues, and a lack of understanding of the difficulties involved in handling the drugs were all considered as risk areas for errors. Organizational hazards were related to the ability to control the delegation, the standard of education, and safety awareness among staff members. Safety issues relating to technology involved devices for handling prescription cards and when staff were not included in the development process of new technological aids. A lack of staff and the lack of time to act safely in the care of the elderly were also perceived as safety hazards, particularly with the non-licensed staff working in nursing homes. CONCLUSIONS: The staff working in nursing homes perceive that the risks due to medication management are mainly caused by human limitations or technical deficiencies. Organizational factors, such as working conditions, can often facilitate the occurrence of malpractice. To minimize mistakes, care managers need to have a systemwide perspective on safety issues, where organizational issues are essential.

Boron phenyl alanine targeted ionic liquid decorated chitosan nanoparticles for mitoxantrone delivery to glioma cell line.

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC50 than the free MTO, and the BPA-targeted NPs have lower IC50 and better cellular uptake than non-targeted NPs in U87MG cells. More studies on this promising formula are on the way, and the results will be published soon.

Ligand-Conformer-Induced Formation of Zirconium-Organic Framework for Methane Storage and MTO Product Separation.

In pursuit of novel adsorbents with efficient adsorptive gas storage and separation capabilities remains highly desired and challenging. Although the documented zirconium-tricarboxylate-based metal-organic frameworks (MOFs) have displayed a variety of topologies encompassing underlying and geometry mismatch ones, the employed organic linkers are exclusively rigid and poorly presenting one type of conformation in the resultant structures. Herein, a used and semirigid tricarboxylate ligand of H3 TATAB was judiciously selected to isolate a zirconium-based spe-MOF after the preliminary discovery of srl-MOF. Single-crystal X-ray diffraction reveals that the fully deprotonated TATAB linker in spe-MOF exhibits two distinct conformers, concomitant with popular Oh and rare S6 symmetrical Zr6 molecular building blocks, generating an unprecedented (3,3,12,12)-c nondefault topology. Specifically, the spe-MOF exhibits structurally higher complexity, hierarchical micropores, open metal sites free and rich electronegative groups on the pore surfaces, leading to relatively high methane storage capacity without considering the missing-linker defects and efficient MTO product separation performance.

Circ-MTO1 correlates with favorable prognosis and inhibits cell proliferation, invasion as well as miR-17-5p expression in prostate cancer.

BACKGROUND: This study aimed to investigate circular RNA-mitochondrial tRNA translation optimization 1 (circ-MTO1) expression in tumor tissue and its correlation with clinical characteristics and survival profiles, as well as its effect on cancer cell functions in prostate cancer. METHODS: A total of 298 primary prostate cancer patients were included. Reverse transcription-quantitative polymerase chain reaction was conducted to evaluate circ-MTO1 expression in tumor tissue and paired adjacent tissue. Disease-free survival (DFS) and overall survival (OS) were recorded. In in vitro experiment, prostate cancer cells were transfected with circ-MTO1 over-expression and negative-control over-expression plasmids. Then cell proliferation, cell invasion and miR-630 as well as miR-17-5p expressions in prostate cancer cells were detected. RESULTS: Circular RNA-mitochondrial tRNA translation optimization 1 expression was downregulated in tumor tissue compared with paired adjacent tissue (P < .001) in patients with prostate cancer. Circ-MTO1 high expression in tumor tissue was correlated with decreased pathological T stage (P = .001) as well as lower pathological N stage (P = .020). As for survival profiles, the DFS (P = .006) and OS (P = .018) were both longer in patients who had circ-MTO1 high expression compared with patients who had circ-MTO1 low expression. In addition, circ-MTO1 high expression independently predicted favorable DFS and OS. Besides, further in vitro experiments illustrated that circ-MTO1 inhibited proliferation (P < .05) and invasion (P < .05) as well as downregulated miR-17-5p expression in prostate cancer cells (P < .05). CONCLUSION: Circ-MTO1 correlates with decreased pathological T/N stage and favorable survival profiles, and it also inhibits cell proliferation, invasion as well as miR-17-5p expression in prostate cancer.

High Ethylene Selectivity in Methanol-to-Olefin (MTO) Reaction over MOR-Zeolite Nanosheets.

Precisely controlled crystal growth endows zeolites with special textural and catalytic properties. A nanosheet mordenite zeolite with a thickness of ca. 11 nm, named as MOR-NS, has been prepared using a well-designed gemini-type amphiphilic surfactant as bifunctional structure-directing agent (SDA). Its benzyl diquarternary ammonium cations structurally directed the formation of MOR topology, whereas the long and hydrophobic hexadecyl tailing group prevented the extensive crystal growth along b axis. This kind of orientated crystallization took place through the inorganic-organic interaction between silica species and SDA molecules present in the whole process. The thin MOR nanosheets, with highly exposed (010) planes and 8-membered ring (MR) windows, exhibited a much improved ethylene selectivity (42.1 %) for methanol-to-olefin (MTO) reactions when compared with conventional bulk MOR crystals (3.3 %).

Impact of Zeolite Framework Composition and Flexibility on Methanol-To-Olefins Selectivity: Confinement or Diffusion?

The methanol-to-olefins reaction catalyzed by small-pore cage-based acid zeolites and zeotypes produces a mixture of short chain olefins, whose selectivity to ethene, propene and butene varies with the cavity architecture and with the framework composition. The product distribution of aluminosilicates and silicoaluminophosphates with the CHA and AEI structures (H-SSZ-13, H-SAPO-34, H-SSZ-39 and H-SAPO-18) has been experimentally determined, and the impact of acidity and framework flexibility on the stability of the key cationic intermediates involved in the mechanism and on the diffusion of the olefin products through the 8r windows of the catalysts has been evaluated by means of periodic DFT calculations and ab initio molecular dynamics simulations. The preferential stabilization by confinement of fully methylated hydrocarbon pool intermediates favoring the paring pathway is the main factor controlling the final olefin product distribution.

Water-Induced Structural Dynamic Process in Molecular Sieves under Mild Hydrothermal Conditions: Ship-in-a-Bottle Strategy for Acidity Identification and Catalyst Modification.

Water is the most important substance in nature. Imitating the formation of natural materials, molecular sieves have been synthesized under hydrothermal conditions and applied in industry. Herein, we reveal an unforeseen observation on a very special water-induced structural dynamic process of these materials. Dynamic and reversible breaking and forming of T-O-T bonds in silicoaluminophosphate (SAPO) occurs through interactions between gaseous water and the molecular-sieve framework under mild hydrothermal conditions and is confirmed by detection of the incorporation of 17 O from H2 17 O into molecular-sieve framework. Encapsulation of the bulky molecules trimethylphosphine and pyridine (kinetic diameters much larger than the pore size of SAPO-34) into CHA cavities consolidated the water-induced dynamic process. Consequently, new insights into the dynamic features of molecular sieves in water are provided. The ship-in-a-bottle strategy based on these findings also open new fields for fine acidity identification and gives extra boost in shape-selective catalysis.

A simple and efficient automated cGMP-compliant radiosynthesis of [11 C]metomidate using solid phase extraction cartridge purification.

[11 C]metomidate ([11 C]MTO) is a radiotracer widely used to detect disorders of adrenocortical origin by positron emission tomography (PET) imaging. [11 C]MTO PET/computed tomography (PET/CT) is considered a sensitive and specific noninvasive alternative to adrenal vein sampling (AVS) in the management of primary hyperaldosteronism (PHA). Herein, we report a reliable automated procedure for the routine manufacturing of [11 C]MTO in current good manufacturing practice (cGMP) conditions on the commercial Synthra MeIPlus Loop Vessel synthesizer. The method is based on a combination of the captive-solvent 11 C-methylation of the carboxylate salt 1b of the MTO precursor 1a followed by solid phase extraction (SPE) cartridge purification methodology, which substitutes HPLC purification of the crude reaction mixture. Starting from 45 GBq [11 C]CO2 at the end of bombardment (EOB), 3 GBq of pure [11 C]MTO was produced in 18 minutes with 12% decay corrected radiochemical yield (RCY) at the end of synthesis (EOS) and with the modest molar activity of 13 GBq/µmol at the time of application. Each dose produced met all established quality control (QC) criteria. The method can easily be implemented into other commercial automated radiosynthesizers for manufacturing carbon-11 labeled radiotracers.

Tuning Zeolite Properties for a Highly Efficient Synthesis of Propylene from Methanol.

A series of nanosized ZSM-5 samples was synthesized at 170, 150, 120, and 100 °C. Experimental data show that the decrease of crystallization temperature leads to significant changes in zeolite properties. Crystals synthesized at 100 °C exhibit many framework defects with lower acid-site density, strength, and a larger external surface area. The selectivity to light olefins and the propylene-to-ethylene ratio increases as the crystallization temperature decreases. A propylene-to-ethylene ratio of above 6 with the highest selectivity to propylene of 53 % was obtained over ZSM-5 catalyst prepared at 100 °C. The stability of the nanosized zeolite in methanol to olefins (MTO) was also improved compared to the industrial sample with a similar Si/Al ratio. This catalytic performance is a result of the decrease in the acid-site density, strength, and the crystals' size, providing a shorter diffusion path and larger external surface area. The presence of structural defects and a different external surface in the crystals has been shown to play an important role in the MTO catalyst performance.

The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome.

We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.

Severe respiratory complex III defect prevents liver adaptation to prolonged fasting.

BACKGROUND & AIMS: Next generation sequencing approaches have tremendously improved the diagnosis of rare genetic diseases. It may however be faced with difficult clinical interpretation of variants. Inherited enzymatic diseases provide an invaluable possibility to evaluate the function of the defective enzyme in human cell biology. This is the case for respiratory complex III, which has 11 structural subunits and requires several assembly factors. An important role of complex III in liver function is suggested by its frequent impairment in human cases of genetic complex III defects. METHODS: We report the case of a child with complex III defect and acute liver dysfunction with lactic acidosis, hypoglycemia, and hyperammonemia. Mitochondrial activities were assessed in liver and fibroblasts using spectrophotometric assays. Genetic analysis was done by exome followed by Sanger sequencing. Functional complementation of defective fibroblasts was performed using lentiviral transduction followed by enzymatic analyses and expression assays. RESULTS: Homozygous, truncating, mutations in LYRM7 and MTO1, two genes encoding essential mitochondrial proteins were found. Functional complementation of the complex III defect in fibroblasts demonstrated the causal role of LYRM7 mutations. Comparison of the patient's clinical history to previously reported patients with complex III defect due to nuclear DNA mutations, some actually followed by us, showed striking similarities allowing us to propose common pathophysiology. CONCLUSIONS: Profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting leading to severe lactic acidosis, hypoglycemia, and hyperammonemia, potentially leading to irreversible brain damage. LAY SUMMARY: The diagnosis of rare genetic disease has been tremendously accelerated by the development of high throughput sequencing technology. In this paper we report the investigations that have led to identify LYRM7 mutations causing severe hepatic defect of respiratory complex III. Based on the comparison of the patient's phenotype with other cases of complex III defect, we propose that profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting.

Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant.

We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease.