ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.
Predicting instead of only reacting to the properties of objects we grasp is crucial to dexterous object manipulation. Although we normally plan our grasps according to well-learned associations, we rely on implicit sensorimotor memories when we learn to interact with novel or ambiguous objects. However, little is known about the influence of sensorimotor predictions on subsequent perception and action. Here, young and elderly subjects repeatedly lifted an object in which the center of mass (CoM) was randomly varied between trials straight upward with the aim of preventing object tilts. After each lift, subjects indicated the location of the perceived CoM and reported how heavy the object felt. Surprisingly, we found that sensorimotor torque memories eventually causing initial lifting errors had substantial effects on the perception of torques, weight, and the torque planning for the next lift. Whereas subjects tended to partly retain their previous erroneous sensorimotor memories (instead of solely relying on the previously encountered torque for the upcoming motor plan), they perceived encountered torques to be stronger when they erroneously predicted them. Additionally, we found that torque prediction errors, as well as the actual torques, made the object feel heavier. By contrast, perception did not influence upcoming motor control. There were no major differences observed between the age groups. The sensorimotor impact on torque perception can be explained by internal feedforward prediction highlighting task-relevant errors, while the partial retention and adaptation of sensorimotor torque memories is reconciled with the trial-to-trial learning rule for motor adaptation. NEW & NOTEWORTHY The current study is the first to demonstrate in an object manipulation task in uncertainty that errors in the sensorimotor prediction of torques influence the perception of both torques and weight, whereas sensorimotor torque memories are partly retained and partly adapted to planning errors. Our results provide novel insights into the predictive mechanisms underpinning the common everyday task of object manipulation and further support theories about the predictive modulation of perception established in other neuroscientific disciplines.
Helicobacter pylori infects up to 50% of the human population worldwide. The infection occurs predominantly in childhood and persists for decades or a lifetime. H. pylori is believed to be transmitted from person to person. However, tremendous genetic diversity has been reported for these bacteria. In order to gain insight into the epidemiological basis of this phenomenon, we performed molecular typing of H. pylori isolates from different families. Fifty-nine H. pylori isolates from 27 members of nine families were characterized by using restriction fragment length polymorphism analysis of five PCR-amplified genes, by pulsed-field gel electrophoresis (PFGE) of chromosomal DNA, and byvacA and cagA genotyping. The 16S rRNA gene exhibited little allelic variation, as expected for a unique bacterial species. In contrast, the vacA, flaA,ureAB, and lspA-glmM genes were highly polymorphic, with a mean genetic diversity of 0.83, which exceeds the levels recorded for all other bacterial species. In conjunction with PFGE, 59 H. pylori isolates could be differentiated into 21 clonal types. Each individual harbored only one clone, occasionally with a clonal variant. Identical strains were always found either between siblings or between a mother and her children. Statistical analysis revealed clonality of population structure in all isolates. The results of this study suggest the possible coexistence of a large array of clonal lineages that are evolving in each individual in isolation from one another. Transmission appears to occur primarily from mother to child and perhaps between siblings.
Iran has a complex dragonfly fauna influenced by contacts and overlaps of different geographical zones. Its fauna is dominated by Eurosiberian taxa. However, the SE Province Sistãn-va-Baluchestãn is rich in oriental species, many of which having their western distribution limit in Iran. In NE-Iran, Irano-Turanian elements live and in the S- and SW-Iran African species are found. The Iranian Odonata fauna seems well studied, however, a closer look reveals many uncertainties and confusion, some records coming clearly from misidentification whereas other, which were missing proofs of correct identification remains to be confirmed. Even today, every new collecting trip reveals species new for Iran whereas species new for science are still detected, although rarely. In this checklist we include seven taxa new for Iran: Stylurus ubadschii (although a male of uncertain origin is recorded in Schmidt (1954), Ischnura senegalensis (although two uncertain records were published by Martin (1912) and Schmidt (1954), Coenagrion ponticum, C. lunulatum, C. pulchellum, Lestes macrostigma, and Calopteryx splendens tschaldirica. We critically checked all available data, including all published records. Fourteen taxa have been rejected, or placed in the category for need of confirmation. Till the end of 2017, 100 autochthonous taxa of dragonflies and two migratory species could be confirmed to be or have been present in Iran. We provide distribution maps, created after evaluation of published data and containing our own data from 12 trips to Iran, travelling over 35000 km in the country. Over 200 new localities are integrated. Taxonomic confusion is reduced by rejecting the following taxa for Iran: Calopteryx splendens mingrelica, C. hyalina, Erythromma najas, Aeshna cyanea, Gomphus davidi, and Sympetrum sinaiticum. We regard the taxa Gomphus amseli and G. schneiderii transcaspicus as synonyms of G. schneiderii, and Onychogomphus forcipatus lucidostriatus as a synonym of O. f. albotibialis.
In order to develop an electro-optic waveguide, Pb(Zr, Ti)O3 ceramic ferroelectric thin films were elaborated by a modified sol-gel process on glass substrate. In the aim to study the optical properties of the PZT films, an accurate refractive index and thickness measurement apparatus was set up, which is called M-lines device. An evaluation of experimental uncertainty and calculation of the precision of the refractive index and thickness were developed on PZT layers. Two different processes of PZT elaboration were made and studied with this apparatus. The reproducibility of one fabrication process was tested and results are presented in this paper
Amoxicillin is often implemented in Helicobacter pylori treatment protocols. To date, amoxicillin-resistant H. pylori strains have rarely been detected, and only a total of 14 have been reported in the literature (1). Conspicuously, complete loss of the resistant phenotype was observed after these strains were stored at Ϫ80°C. Only one amoxicillin-resistant H. pylori strain has been isolated, in The Netherlands, in which in contrast, the amoxicillin resistance remained stable after repeated cycles of freezing and culture (5). The MIC for this strain was 8 g/ml, which is relatively low. Since 1996, we have isolated seven H. pylori strains exhibiting high-level amoxicillin resistance (MIC Ͼ 256 g/ml) (Table 1). Four of these exhibited a stable resistance phenotype (strains ACR3,-4,-5, and-7). Strains ACR1,-2, and-4 were isolated from two 11-year-old girls and one 15-year-old girl with recurrent abdominal pain. They received triple therapy in
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