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Quantity and quality of motor exploration are proposed to be fundamental for infant motor development. However, it is still not clear what types of motor exploration contribute to learning. To determine whether changes in quantity of leg movement and/or variability of leg acceleration are related to performance in a contingency learning task, twenty 6-8-month-old infants with typical development participated in a contingency learning task. During this task, a robot provided reinforcement when the infant's right leg peak acceleration was above an individualized threshold. The correlation coefficient between the infant's performance and the change in quantity of right leg movement, linear variability, and nonlinear variability of right leg movement acceleration from baseline were calculated. Simple linear regression and multiple linear regression were calculated to explain the contribution of each variable to the performance individually and collectively. We found significant correlation between the performance and the change in quantity of right leg movement (r = 0.86, p < 0.001), linear variability (r = 0.71, p < 0.001), and nonlinear variability (r = 0.62, p = 0.004) of right leg movement acceleration, respectively. However, multiple linear regression showed that only quantity and linear variability of leg movements were significant predicting factors for the performance ratio (p < 0.001, adjusted R 2 = 0.94). These results indicated that the quantity of exploration and variable exploratory strategies could be critical for the motor learning process during infancy., Competing Interests: Conflict of interest statement All the authors do not claim any conflict of interest which might be perceived as posing a conflict or bias., (Copyright © 2022 Elsevier Inc. All rights reserved.)

As improvements in medicine lower infant mortality rates, more infants with neuromotor challenges survive past birth. The motor, social, and cognitive development of these infants are closely interrelated, and challenges in any of these areas can lead to developmental differences. Thus, analyzing one of these domains - the motion of young infants - can yield insights on developmental progress to help identify individuals who would benefit most from early interventions. In the presented data collection, we gathered day-long inertial motion recordings from N = 12 typically developing (TD) infants and N = 24 infants who were classified as at risk for developmental delays (AR) due to complications at or before birth. As a first research step, we used simple machine learning methods (decision trees, k-nearest neighbors, and support vector machines) to classify infants as TD or AR based on their movement recordings and demographic data. Our next aim was to predict future outcomes for the AR infants using the same simple classifiers trained from the same movement recordings and demographic data. We achieved a 94.4% overall accuracy in classifying infants as TD or AR, and an 89.5% overall accuracy predicting future outcomes for the AR infants. The addition of inertial data was much more important to producing accurate future predictions than identification of current status. This work is an important step toward helping stakeholders to monitor the developmental progress of AR infants and identify infants who may be at the greatest risk for ongoing developmental challenges.

Physical rehabilitation therapies for children present a challenge, and its success-the improvement of the patient's condition-depends on many factors, such as the patient's attitude and motivation, the correct execution of the exercises prescribed by the specialist or his progressive recovery during the therapy. With the aim to increase the benefits of these therapies, social humanoid robots with a friendly aspect represent a promising tool not only to boost the interaction with the pediatric patient, but also to assist physicians in their work. To achieve both goals, it is essential to monitor in detail the patient's condition, trying to generate user profile models which enhance the feedback with both the system and the specialist. This paper describes how the project NAOTherapist-a robotic architecture for rehabilitation with social robots-has been upgraded in order to include a monitoring system able to generate user profile models through the interaction with the patient, performing user-adapted therapies. Furthermore, the system has been improved by integrating a machine learning algorithm which recognizes the pose adopted by the patient and by adding a clinical reports generation system based on the QUEST metric.

The scarcity of liver donors has increased the necessity to closely select recipients to improve liver transplantation outcomes. If we were able to recognize those recipients with the best outcomes, then this could result in a better and more accurate selection of our donors. Hemoderivate transfusion is one of the main important factors to analyse. We reviewed the data of all of our liver transplant recipients from May 1998 to December 2013 and selected 888 patients with complete records. We divided these patients into 5 groups to get a better selection. We found differences between these groups with respect to the following: recipient age at the time of transplantation, percentage of patients with hepatocarcinoma, and those with hepatitis C virus (HCV)-related etiology. Also, intensive care unit (ICU) time and the need for retransplantation were distinctive factors with observable differences between our groups. With respect to model for end-stage liver disease (MELD) score, the groups were clearly defined by their mean MELD score, finding significant statistical differences between these groups with respect to this score. We also found a significant relationship between MELD scores and survival in the different groups. This is also the first review in which the MELD score and intraoperative transfusion requirements are well associated with patient and graft survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Traditional methods of rehabilitation require continuous attention of therapists during the therapy sessions. This is a hard and expensive task in terms of time and effort. In many cases, the therapeutic objectives cannot be achieved due to the overwork or the difficulty for therapists to plan accurate sessions according to the medical criteria. For this purpose, a wide range of studies is opened in order to research new ways of rehabilitation, as in the field of social robotics. This work presents the current state of the THERAPIST project. Our main goal is to develop a cognitive architecture which provides a robot with enough autonomy to carry out an upper-limb rehabilitation therapy for patients with physical impairments, such as Cerebral Palsy and Obstetric Brachial Plexus Palsy.

Background: Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data., Objective: To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma., Methods: ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine., Results: ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086., Conclusions: These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.

Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.

Poh1 deubiquitinase activity is required for proteolytic processing of polyubiquitinated substrates by the 26S proteasome, linking deubiquitination to complete substrate degradation. Poh1 RNA interference (RNAi) in HeLa cells resulted in a reduction in cell viability and an increase in polyubiquitinated protein levels, supporting the link between Poh1 and the ubiquitin proteasome pathway. To more specifically test for any requirement of the zinc metalloproteinase motif of Poh1 to support cell viability and proteasome function, we developed a RNAi complementation strategy. Effects on cell viability and proteasome activity were assessed in cells with RNAi of endogenous Poh1 and induced expression of wild-type Poh1 or a mutant form of Poh1, in which two conserved histidines of the proposed catalytic site were replaced with alanines. We show that an intact zinc metalloproteinase motif is essential for cell viability and 26S proteasome function. As a required enzymatic component of the proteasome, Poh1 is an intriguing therapeutic drug target for cancer.

Adenine phosphoribosyltransferase plays a role in purine salvage by catalyzing the direct conversion of adenine to adenosine monophosphate. The involvement of the purine salvage pathway in tumor proliferation and angiogenesis makes adenine phosphoribosyltransferase a potential target for oncology drug discovery. We have expressed and characterized recombinant, N-terminally His-tagged human adenine phosphoribosyltransferase. Two assay formats were assessed for use in a high throughput screen: a spectrophotometric-based enzyme-coupled assay system and a radiometric ionic capture scintillation proximity bead assay format. Ultimately, the scintillation proximity assay format was chosen because of automated screening compatibility limitations of the coupled assay. We describe here the biochemical characterization of adenine phosphoribosyltransferase and the development of a robust, homogeneous, 384-well assay suitable for high throughput screening.

Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a G protein-coupled receptor activated by prostaglandin D(2) (PGD(2)), has been identified as a receptor expressed on cell types critical to the pathogenesis of asthma. The cDNA encoding guinea pig CRTH2 was cloned and mRNA expression examined in selected tissues. Transcript profiling of guinea pig CRTH2 indicated relatively high levels of expression in bone marrow, intermediate levels in brain and relatively low levels in lung, spleen, thymus, lymph node, etc. Characterization of the molecular pharmacology of guinea pig CRTH2 revealed that guinea pig CRTH2 exhibited a greater affinity for Delta(12)-PGJ(2), a stable PGD(2) metabolite relative to human CRTH2. The CRTH2 selective agonists 13,14-dihydro-15-keto PGD(2) and Delta(12)-PGJ(2) induced the recruitment of eosinophils following intradermal administration of these ligands in guinea pigs. Chemotaxis of guinea pig eosinophils was elicited by either PGD(2) or Delta(12)-PGJ(2), and was abolished by a CRTH2-specific antagonist. These results indicate that PGD(2) and the stable metabolite, Delta(12)-PGJ(2), play important roles in CRTH2 activation in the guinea pig.

These protocols construct a representative small-insert genomic DNA library in a phagemid vector. First, size-selected DNA fragments are ligated into a phagemid vector. In the second protocol, the resulting small-insert phagemid library is propagated in a bacterial strain combining mutations at the dut and ung loci, which permit incorporation of uracil in place of thymidine during DNA replication. Infection of the phagemid library with M13 helper phage permits recovery of this library as single-stranded DNA (ssDNA). Finally, this uracil-substituted ssDNA is used as a template for primer extension using an oligonucleotide whose sequence corresponds to the STR class of interest [e.g., (GATA)10] as primer. The products of this primer-extension reaction are transformed into an E. coli strain maintaining wild-type genes at the dut and ung loci. Under these conditions, uracil-substituted ssDNA will be restricted from growing by the host-encoded uracil-N-glycosylase, while the primer-extended products are capable of replicating.

The association of subclasses of Alu repetitive elements with various classes of trinucleotide and tetranucleotide microsatellites was characterized as a first step toward advancing our understanding of the evolution of microsatellite repeats. In addition, information regarding the association of specific classes of microsatellites with families of Alu elements was used to facilitate the development of genetic markers. Sequences containing Alu repeats were eliminated because unique primers could not be designed. Various classes of microsatellites are associated with different classes of Alu repeats. Very abundant and poly(A)-rich microsatellite classes (ATA, AATA) are frequently associated with an evolutionarily older subclass of Alu repeats, AluSx, whereas most of GATA and CA microsatellites are associated with a recent Alu subfamily, AluY. Our observations support all three possible mechanisms for the association of Alu repeats to microsatellites. Primers designed using a set of sequences from a particular microsatellite class showed higher homology with more sequences of that class than probes designed for other classes. We developed an efficient method of prescreening GGAA and ATA microsatellite clones for Alu repeats with probes designed in this study. We also showed that Alu probes labeled in a single reaction (multiplex labeling) could be used efficiently for prescreening of GGAA clones. Sequencing of these prescreened GGAA microsatellites revealed only 5% Alu repeats. Prescreening with primers designed for ATA microsatellite class resulted in the reduction of the loss of markers from approximately 50% to 10%. The new Alu probes that were designed have also proved to be useful in Alu-Alu fingerprinting.

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q. We have identified four novel HNF-1alpha missense mutations in MODY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in MODY3. We observed no HNF-1alpha mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes.

The mutated gene responsible for the tubby obesity phenotype has been identified by positional cloning. A single base change within a splice donor site results in the incorrect retention of a single intron in the mature tub mRNA transcript. The consequence of this mutation is the substitution of the carboxy-terminal 44 amino acids with 24 intron-encoded amino acids. The normal transcript appears to be abundantly expressed in the hypothalamus, a region of the brain involved in body weight regulation. Variation in the relative abundance of alternative splice products is observed between inbred mouse strains and appears to correlate with an intron length polymorphism. This allele of tub is a candidate for a previously reported diet-induced obesity quantitative trait locus on mouse chromosome 7.

Two thousand nine hundred and thirty-one tri- and tetranucleotide short tandem repeat polymorphisms (STRPs) developed by the Cooperative Human Linkage Center were assigned to chromosomes using the NIGMS somatic cell hybrid mapping panel 2 and an efficient pooling strategy. Approximately 82% of all STRPs tested were assigned by this method, with 96.7% accuracy. Many of the single chromosome cell lines contained portions of additional chromosomes, confirming previous reports. The cell lines for chromosomes 6, 14, and 20 contained extensive portions of other chromosomes. Five previously unreported chromosomal contaminants were identified and are reported. A new pooling strategy was designed to minimize ambiguous assignments.

The expansion of a (CAG/CTG)n triplet repeat has been found to be associated with at least seven genetic diseases, suggesting that this mechanism of disease may be fairly common. To accelerate the discovery of new loci containing (CAG/CTG)n triplet expansions, we have isolated numerous genomic clones containing this class of repeats. We have developed 338 sequence-tagged sites (STSs) containing (CAG/CTG)n repeat sequences. Two hundred ninety-nine STSs were unambiguously assigned to chromosomes, and 89 of the total were assigned to YACs. The 141 STSs that were developed based on (CAG/CTG)n repeats of at least seven units were genotyped on four reference CEPH individuals to estimate their polymorphic quality.

We report a collection of tri- and tetranucleotide repeat sequence polymorphic markers used to construct genome-wide human linkage maps. Using a strategy of marker selection to create libraries highly enriched for the presence of specific tandem repeat elements, we have developed over 2000 high heterozygosity, easy-to-use tri- and tetranucleotide short tandem repeat polymorphisms (STRPs). To date, over 1300 of these markers have been genotyped on the CEPH reference families. Additional STRPs were assigned to chromosomes using human monochromosomal somatic cell hybrids. The linkage maps constructed with these markers have been integrated with other CEPH genotypes into a comprehensive high density linkage map. These STRPs have been shown to be robust for genotyping in a variety of laboratories using a variety of methods. The high quality of these STRPs makes them ideal candidates for use in genome-wide linkage searches. The integration of these markers with physical mapping reagents and other genetic markers will create a resource for moving from genome-wide linkage searches to rapid sublocalization of disease loci.

A bovine genomic phagemid library was constructed with randomly sheared DNA. Enrichment of this single-stranded DNA library with CA or GT primers resulted in 45% positive clones. The 14% of positive clones with (CA.GT) > 12, and not containing flanking repetitive elements, were sequenced, and the efficiency of marker production was compared with random M13 bacteriophage libraries. Primer sequences and genotyping information are presented for 390 informative bovine microsatellite markers. The genomic frequency for 11 tri- and tetranucleotide repeats was estimated by hybridization to a lambda genomic library. Only GCT, GGT, and GGAT were estimated to have a frequency of > 100 per genome. Enrichment of the phagemid library for these repeats failed to provide a viable source of microsatellite markers in the bovine. Comparison of map interval lengths between 100 markers from the enriched library prepared from randomly sheared DNA and M13 bacteriophage libraries prepared from Mbo1 restriction digests suggested no bias in skeletal genomic coverage based on source of small insert DNA. In conclusion, enrichment of the bovine phagemid library provides a sufficient source of microsatellites so that small repeat lengths and flanking repetitive sequences common in the bovine can be eliminated, resulting in a high percentage of informative markers.

Genetic markers based upon PCR amplification of short tandem repeat-containing sequence tagged sites (STSs) have become the standard for genetic mapping. We have completed a survey based on the direct isolation of representative members of each of the 10 trinucleotide repeat classes to determine their relative abundance, repeat size distribution, and general utility as genetic markers. Trinucleotide repeats, depending on the repeat class, are one to two orders of magnitude less frequent than (AC)n repeats. The average size of trinucleotide repeats sequenced was less than 15 repeat units in length, and only three of the STSs developed for this study demonstrated more than 25 repeats units. The (AAT)n class of repeats are the most abundant and also the most frequently polymorphic. Other classes of trinucleotide repeat classes observed to be frequently polymorphic include (AAC)n, (ACT)n, (ATC)n and (AAG)n; however, the relative abundance of these classes is less than that observed for the (AAT)n class of repeats. Based upon this initial survey, we have initiated saturation cloning of the (AAT)n class of repeats. At the time of submission of this manuscript, we have developed, as part of the Cooperative Human Linkage Center (CHLC), more than 415 new high heterozygosity (AAT)n genetic markers (more than two alleles in four individuals) and 200 new low heterozygosity (AAT)n STSs from this larger screening effort combined with the initial survey.

In this report, we describe the successful application of a rapid and efficient procedure, based on subtractive hybridization and PCR amplification, for generating microsatellite-based markers directly from yeast artificial chromosomes (YACs). This strategy, termed MATS (marker addition through subtraction), exploits the fact that the only difference between a yeast host strain harboring a YAC and the host strain alone is the artificial chromosome. Given the low complexity of the yeast genome and relatively large target size presented by a YAC, only a single round of subtraction is required before amplification of the target sequences (YAC) and cloning into a plasmid vector for further analysis. Several key steps have been designed to achieve optimal subtraction and to obtain preferential amplification and recovery of the target sequences. Methods for efficient construction of small insert libraries and rapid, nonradioactive screening have also been integrated into the protocol. Using a 750-kb YAC as a target, we identified a minimum of 14 unique microsatellite containing clones, leading to the development of 12 polymorphic STSs (sequence-tagged sites). These new markers will facilitate the genetic localization of targeted locus and allow the accurate ordering by STS content mapping of a cloned contig spanning the interval. In addition to the utility of this approach in positional cloning, this strategy may provide an approach for filling gaps in the emerging genetic maps.