Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation

The bacterial and archaeal communities of flies, manure, lagoons, and troughs at a working dairy

BackgroundFundamental investigations into the location, load, and persistence of microbes, whether beneficial or detrimental, are scarce. Many questions about the retention and survival of microbes on various surfaces, as well as the load necessary for spread, exist. To answer these questions, we must know more about where to find various microbes and in what concentrations, the composition of the microbial communities, and the extent of dissemination between various elements. This study investigated the diversity, composition, and relative abundance of the communities associated with manure, lagoons, troughs, house flies, and stable flies present at a dairy, implementing two different free-stall management systems: flow-through and cross-vent. Shotgun metagenomics at the community level was used to compare the microbiomes within the dairy, allowing confident interpretation at the species level.ResultsThe results showed that there were significant difference in microbial composition between not only each of the dairy elements but also management styles. The primary exceptions were the microbiomes of the house fly and the stable fly. Their compositions heavily overlapped with one another, but interestingly, not with the other components sampled. Additionally, both species of flies carried more pathogens than the other elements of the dairy, indicating that they may not share these organisms with the other components, or that the environments offered by the other components are unsatisfactory for the survival of some pathogens..ConclusionThe lack of overlapping pathogen profiles suggests a lack of transfer from flies to other dairy elements. Dairy health data, showing a low incidence of disease, suggests minimal sharing of bacteria by the flies at a level required for infection, given the health program of this dairy. While flies did carry a multitude of pathogenic bacteria, the mere presence of the bacteria associated with the flies did not necessarily translate into high risk leading to morbidity and mortality at this dairy. Thus, using flies as the sole sentinel of dairy health may not be appropriate for all bacterial pathogens or dairies

Association of Diabetic Ketoacidosis and HbA1c at Onset with Year-Three HbA1c in Children and Adolescents with Type 1 Diabetes: Data from the International SWEET Registry

Objective: To establish whether diabetic ketoacidosis (DKA) or HbA1c at onset is associated with year-three HbA1c in children with type 1 diabetes (T1D). Methods: Children with T1D from the SWEET registry, diagnosed <18 years, with documented clinical presentation, HbA1c at onset and follow-up were included. Participants were categorized according to T1D onset: (a) DKA (DKA with coma, DKA without coma, no DKA); (b) HbA1c at onset (low [<10%], medium [10 to <12%], high [≥12%]). To adjust for demographics, linear regression was applied with interaction terms for DKA and HbA1c at onset groups (adjusted means with 95% CI). Association between year-three HbA1c and both HbA1c and presentation at onset was analyzed (Vuong test). Results: Among 1420 children (54% males; median age at onset 9.1 years [Q1;Q3: 5.8;12.2]), 6% of children experienced DKA with coma, 37% DKA without coma, and 57% no DKA. Year-three HbA1c was lower in the low compared to high HbA1c at onset group, both in the DKA without coma (7.1% [6.8;7.4] vs 7.6% [7.5;7.8], P = .03) and in the no DKA group (7.4% [7.2;7.5] vs 7.8% [7.6;7.9], P = .01), without differences between low and medium HbA1c at onset groups. Year-three HbA1c did not differ among HbA1c at onset groups in the DKA with coma group. HbA1c at onset as an explanatory variable was more closely associated with year-three HbA1c compared to presentation at onset groups (P = .02). Conclusions: Year-three HbA1c is more closely related to HbA1c than to DKA at onset; earlier hyperglycemia detection might be crucial to improving year-three HbA1c.info:eu-repo/semantics/publishedVersio

Attractor dynamics approach to joint transportation by autonomous robots: theory, implementation and validation on the factory floor

This paper shows how non-linear attractor dynamics can be used to control teams of two autonomous mobile robots that coordinate their motion in order to transport large payloads in unknown environments, which might change over time and may include narrow passages, corners and sharp U-turns. Each robot generates its collision-free motion online as the sensed information changes. The control architecture for each robot is formalized as a non-linear dynamical system, where by design attractor states, i.e. asymptotically stable states, dominate and evolve over time. Implementation details are provided, and it is further shown that odometry or calibration errors are of no significance. Results demonstrate flexible and stable behavior in different circumstances: when the payload is of different sizes; when the layout of the environment changes from one run to another; when the environment is dynamice.g. following moving targets and avoiding moving obstacles; and when abrupt disturbances challenge team behavior during the execution of the joint transportation task.- This work was supported by FCT-Fundacao para a Ciencia e Tecnologia within the scope of the Project PEst-UID/CEC/00319/2013 and by the Ph.D. Grants SFRH/BD/38885/2007 and SFRH/BPD/71874/2010, as well as funding from FP6-IST2 EU-IP Project JAST (Proj. Nr. 003747). We would like to thank the anonymous reviewers, whose comments have contributed to improve the paper

Association of tumour microRNA profiling with outcomes in patients with advanced urothelial carcinoma receiving first-line platinum-based chemotherapy

Background: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC). Methods: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin. A miR panel based on relevance for platinum sensitivity and UC was studied by quantitative reverse transcription quantitative PCR (RT–qPCR). Association of progression-free survival (PFS) with miR expression was analysed using cox regression. Selected TFs were chosen by association with the panel of miRs using the Transcription Regulation algorithm (GeneGo MetaCore+MetaDrug version 6.23 build 67496). Bladder cancer (BC) cell lines were used to investigate the previously described role of miR-21 mediating cisplatin sensitivity. Results: The 83 patients had a median PFS of 8 months. In multivariate analysis, higher levels of E2F1 (P=0.01, HR: 1.95 (1.14, 3.33)), miR-21 (P=0.01, HR: 2.01 (1.17, 3.45)) and miR-372 (P=0.05, HR: 1.70 (1.00, 2.89)) were associated with a shorter PFS. In the 8 BC cell lines, miR-21 was not shown to be necessary nor sufficient for modulating cisplatin sensitivity. Conclusions: In metastatic UC patients treated with cisplatin-based therapy, high primary tumour levels of E2F1, miR-21 and miR-372 are associated with poor PFS independent of clinical prognostic factors. The in vitro study could not confirm miR-21 levels role in modulating platinum sensitivity

Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression

Depression is a highly prevalent and recurrent neuropsychiatric disorder associated with alterations in emotional and cognitive domains. Neuroplastic phenomena are increasingly considered central to the etiopathogenesis of and recovery from depression. Nevertheless, a high number of remitted patients experience recurrent episodes of depression, remaining unclear how previous episodes impact on behavior and neuroplasticity and/or whether modulation of neuroplasticity is important to prevent recurrent depression. Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits. Furthermore, treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; however, their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression. Strikingly, cell proliferation arrest compromised the behavior resilience induced by imipramine and buffered the susceptibility to recurrent behavioral changes promoted by fluoxetine. This study shows that previous exposure to a depressive-like episode impacts on the behavioral and neuroanatomical changes triggered by subsequent re-exposure to similar experimental conditions and reveals that the proper control of adult hippocampal neuroplasticity triggered by antidepressants is essential to counteract recurrent depressive-like episodes.FCT (IF/01079/2014). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio