An exploration of visuomotor and perceptual mechanisms in humans and rats.

Neuropsychological, neurophysiological and psychophysical evidence support the notion of two separate and largely independent cortical visual systems: a dorsal system mediating visually guided action and a ventral system mediating object perception and recognition (Goodale & Milner, 1992). This thesis is divided into three parts that explore questions related to the two-visual-systems model, two in humans and one in rats. The first part explores whether dorsal representations are based on the veridical properties of the stimuli or whether they include information produced by filling-in mechanisms of cortical visual areas. All human experiments were carried out with the ELITE and SMART motion tracking systems. Kinematic analysis showed that grasping Kanizsa illusory squares and partly-occluded objects was as accurate as grasping luminance-defined targets and it is concluded that information about interpolated regions is available to the dorsal system for the calibration of the movement parameters. A Vernier acuity task confirmed that the perceptual localization of Kanizsa and luminance-defined contours is not equally accurate in the ventral visual system. The second part explores the effect of target dimensionality on grasping, focusing on the possibility that actions aimed at targets that contain two-dimensional information could be modulated by ventral visual mechanisms. The Diagonal Illusion (DI) was chosen to investigate this possibility because it is entirely the product of three- dimensional objects. The DI exerted an effect on both perception and action, although the latter was smaller, suggesting that the effects of illusions on action previously reported are not attributable to the presence of 2D information and, by implication, that 2D information in the target array does not elicit modulation by the ventral visual system. These conclusions were confirmed by a study that found similar kinematic profiles from grasps aimed at 3D, 2D and 2D-enhanced targets. Control studies ruled out potential confounding effects resulting from curvatures of the stimuli that could have acted as obstacles and from differences in haptic feedback. It is concluded that object-directed action is mediated by dorsal visual mechanisms, irrespective of target dimensionality. The third part seeks to find evidence of ventral visual processing in rats by measuring the perception of visual illusions and object recognition in this species. The aim is to establish whether rats could provide a suitable model to further investigate the dorsal and ventral visual systems. An automated apparatus with a touch-screen and computer generated stimuli was developed to train the animals. The results from the illusion studies are not conclusive as only one out of three groups of rats was able to solve a discrimination with Kanizsa illusory figures. The preliminary results from the object recognition studies are however clearer. Rats were able to use aspect ratio to solve a discrimination with stimuli that varied in size and location suggesting that size- and location-independent object recognition occurs in this species. Probe trials confirmed these results. It is concluded that rats may have visual processes comparable to those occurring in the ventral visual system of humans and primates

Normal and five-fingered hand: comparative X-ray morphometry in the post-natal age

Background: Five-fingered hand (5-FH) with completely developed phalanges is a rare phenotype observed so far only in humans and characterised by three phalanges of the 1st ray. A long-lasting, debated question is if the missing element of the normal hand 1st ray is the metacarpal or the phalanx. In this study, comparative X-rays morphometry of long bones in normal and 5-FH is carried out with the aim to face this question through homology analysis of long bone segments in the transverse and longitudinal line of normal hand and 5-FH. Materials and methods: In the normal hand X-rays (n =20) and in a 5-FH X-rays series (n = 9) the relative length of each segment on the ray total length and the index of growth rate (IGR) were assessed. The calculation of the first parameter in normal hand bi-phalangeal thumb was carried out on the 3rd ray total length in the same hand. Results: The parameters of relative length and the proximal/distal growth rate asymmetry in the post-natal period (assessed through the IGR) confirmed in 5-FH the homology of all the five segment on the transverse line. In the normal control hand, the relative length assessment methodology was biased by the missing segment of the thumb, therefore, the reference to the 3rd ray total length in the same hand (instead of the 1st), allowed the homology analysis of the thumb metacarpal and 1st phalanx with the lateral segments (2nd–5th ray) of the same hand. The 5-FH analysis was used to choose the more appropriate reference ray for the normal hand group. Conclusions: The comparative analysis of relative lengths and IGRs in the two groups suggested homology of the (anatomical) 1st metacarpal with the 2nd–5th proximal phalanges in the same hand and that of the (anatomical) 1st proximal phalanx with the 2nd–5th mid phalanges. These data suggest that the missing segment of the normal hand thumb is the metacarpal

Functional Characterization of Two Mutations Located in the Ligand Binding Domain in the SF1

Purpose: Since SF1 gene mutations located in the ligand binding domain are associated with a wide phenotypic spectrum in 46,XY subjects, the functional and structural characterization of these variations is of great interest. The aim of this study is to evaluate the clinical phenotype, hormonal pattern and molecular studies (genetic, functional data and protein structural analysis) in two non-related 46,XY disorder of sex development (DSD) index patients. Methods: Clinical characteristics, genomic DNA sequencing analysis, protein prediction software study and protein structure analysis, and functional characterization of the mutations was carried out. Results: Both index DSD patients showed a similar phenotype, however several affected members of Family 1 showed variable phenotypes. While in Family 1 a previously reported heterozygous missense point mutation (p.Arg313His) was found, in Family 2 a novel heterozygous missense point mutation (p.Ser303Arg) was detected. Both mutations were predicted to be as “probably damaging”. The transcriptional activity of SF1 mutants p.Arg313His and p.Ser303Arg, studied using two different promoters in two cell lines, exhibited significant reductions of transactivation activity. Structural analysis showed differences between both mutants, such as changes in the flexibility of the receptor backbone and in the tertiary structure around the ligand and in the AF-2 domain. Conclusions: One of these ligand binding domain mutations in SF1 showed phenotypic heterogeneity among family members, while both variations showed similarities in prepubertal phenotype, as well as in damage prediction and experimental decreases in transcriptional activity, but marked differences in structural consequence predictions. Finally the present study reinforces the concept of the wide variability in the clinical phenotype in affected 46,XY DSD patients.Fil: Perez Garrido, Natalia Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marino, R.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ramirez, P.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ciaccio, Marta Graciela Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Costanzo, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Guercio, Gabriela Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Warman, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Minini, L.. Universidad de la República. Facultad de Ciencias; UruguayFil: Portillo Ledesma, S.. Universidad de la República. Facultad de Ciencias; UruguayFil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Coitiño, E. L.. Universidad de la República. Facultad de Ciencias; UruguayFil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Acute scapholunate dissociation diagnosis and treatment

Scapholunate interosseous ligament (SLIL) is the most frequent injured carpal ligament among all the intrinsic wrist ones. The scapholunate (SL) joint kinetics appear to be handled by a more sophisticated complex of intrinsic and extrinsic ligaments: cadaveric studies investigated the role of the long radiolunate (LRL), short radiolunate (SRL), radioscaphoid (RS), and dorsal intercarpal ligament (DIC) in SL joint stability. The most common traumatic mechanism leading to SL lesions is the FOOSH (fall on outstretched hand), with the wrist in extension, ulnar deviation and carpal supination. Defining the clinical stage and the time elapsed since the injury is of utmost importance in planning an effective treatment: an injury is considered as “acute” when time lapse from the trauma to the presentation lies within 6 weeks. This paper will focus on the acute/subacute setting. Acute SL lesions can frequently be misdiagnosed as minor wrist sprains; since early recognition and prompt treatment can lead to better outcomes, a delay in the correct diagnosis is detrimental for clinical results. Furthermore, interrupting the natural progression from SLIL injury to SLAC is of utmost importance. Partial lesions can be treated conservatively with immobilization and proprioceptive reeducation, percutaneous K-wires pinning of SL and SC joints and thermal shrinkage. Complete lesions should be treated operatively; open repair with suture anchors and capsulodesis show good results, even if arthroscopic techniques are now gaining popularity, although further studies with long-term follow-up are needed to evaluate the durability of those procedures

Trialling a microbiome-targeted dietary intervention in children with ADHD—the rationale and a non-randomised feasibility study.

Background Dietary interventions have been previously explored in children with ADHD. Elimination diets and supplementation can produce beneficial behaviour changes, but little is known about the mechanisms mediating change. We propose that these interventions may work, in part, by causing changes in the gut microbiota. A microbiome-targeted dietary intervention was developed, and its feasibility assessed. Methods A non-randomised feasibility study was conducted on nine non-medicated children with ADHD, aged 8–13 years (mean 10.39 years), using a prospective one-group pre-test/post-test design. Participants were recruited from ADHD support groups in London and took part in the 6-week microbiome-targeted dietary intervention, which was specifically designed to impact the composition of gut bacteria. Children were assessed pre- and post-intervention on measures of ADHD symptomatology, cognition, sleep, gut function and stool-sample microbiome analysis. The primary aim was to assess the study completion rate, with secondary aims assessing adherence, adverse events (aiming for no severe and minimal), acceptability and suitability of outcome measures. Results Recruitment proved to be challenging and despite targeting 230 participants directly through support groups, and many more through social media, nine families (of the planned 10) signed up for the trial. The completion rate for the study was excellent at 100%. Exploration of secondary aims revealed that (1) adherence to each aspect of the dietary protocol was very good; (2) two mild adverse events were reported; (3) parents rated the treatment as having good acceptability; (4) data collection and outcome measures were broadly feasible for use in an RCT with a few suggestions recommended; (5) descriptive data for outcome measures is presented and suggests that further exploration of gut microbiota, ADHD symptoms and sleep would be helpful in future research. Conclusions This study provides preliminary evidence for the feasibility of a microbiome-targeted dietary intervention in children with ADHD. Recruitment was challenging, but the diet itself was well-tolerated and adherence was very good. Families wishing to trial this diet may find it an acceptable intervention. However, recruitment, even for this small pilot study, was challenging. Because of the difficulty experienced recruiting participants, future randomised controlled trials may wish to adopt a simpler dietary approach which requires less parental time and engagement, in order to recruit the number of participants required to make meaningful statistical interpretations of efficacy

Human cortical responses to variations of the interocular correlation of binocular signals

The human visual system has an impressive ability to extract tiny differences from the left and right retinal images to produce the perception of depth. Moreover, the perception of depth is robust to a considerable amount of noise between the two images. Both these features of human vision contribute to the effectiveness of 3D imaging systems. Recent study of brain mechanisms for stereo has identified that there are multiple sites within the brain that respond to stereo depth, potentially implying that an effective 3D imaging system must deliver effective stimulation to multiple and differentiated brain systems. Here, we measure the neural responses of the visual cortex when tested a disparity-defined stimulus whose degree of interocular correlation was varied systematically. Neural responses were measured with functional magnetic resonance imaging (fMRI). This approach allowed us to obtain simultaneously measurements of the pattern of behavioral and neural responses to degraded binocular stimulation. Behavioral performance for the correct identification of binocular depth improved as expected with increasing degrees of binocular correlation. By comparison, the Blood Oxygen Level Dependent (BOLD) signal showed no consistent relationship with different levels of interocular correlation, although several of the visual cortical areas were strongly activated by the binocular stimuli. Preliminary analysis suggests that investigations of binocular vision that use fMRI need to adopt a multivariate approach to determine differences in neural responses to disparity-defined stimuli. © 2012 IEEE