Mathematical difficulties as decoupling of expectation and developmental trajectories

Recent years have seen an increase in research articles and reviews exploring mathematical difficulties (MD). Many of these articles have set out to explain the etiology of the problems, the possibility of different subtypes, and potential brain regions that underlie many of the observable behaviors. These articles are very valuable in a research field, which many have noted, falls behind that of reading and language disabilities. Here will provide a perspective on the current understanding of MD from a different angle, by outlining the school curriculum of England and the US and connecting these to the skills needed at different stages of mathematical understanding. We will extend this to explore the cognitive skills which most likely underpin these different stages and whose impairment may thus lead to mathematics difficulties at all stages of mathematics development. To conclude we will briefly explore interventions that are currently available, indicating whether these can be used to aid the different children at different stages of their mathematical development and what their current limitations may be. The principal aim of this review is to establish an explicit connection between the academic discourse, with its research base and concepts, and the developmental trajectory of abstract mathematical skills that is expected (and somewhat dictated) in formal education. This will possibly help to highlight and make sense of the gap between the complexity of the MD range in real life and the state of its academic science

Nature/nurture and the origin of individual differences in mathematics:evidence from infant and behavioural genetics studies

In this chapter, we discuss empirical evidence addressing the nature-nurture debate from two different perspectives: infant studies and behavioural genetics. Current evidence suggests that there are two cognitive systems for encoding numerical information, and perhaps core systems for geometry. However, questions remain about whether these systems are both present at birth and hence the degree of determinism and the mechanisms by which they connect to later mathematics are still far from established. Behavioural genetics studies offer a valuable way to assess the origin of individual differences in mathematical cognition and to discriminate between genetic and environmental contributions. We thus review relevant evidence on core quantitative knowledge, mathematical abilities and cross-domain relations from twin studies. We conclude by suggesting that while there is convincing evidence of nature’s general and specific role in mathematics, it is clear that environment plays a fundamental role too. The real question for the future is not whether mathematics has a natural core but how to optimise the interaction between nature and nurture so that differential domain-specific and domain-general predispositions can meet an ideal environment to blossom into competent mathematics

Psychiatric Disorders and lncRNAs: A Synaptic Match

Psychiatric disorders represent a heterogeneous class of multifactorial mental diseases whose origin entails a pathogenic integration of genetic and environmental influences. Incidence of these pathologies is dangerously high, as more than 20% of the Western population is affected. Despite the diverse origins of specific molecular dysfunctions, these pathologies entail disruption of fine synaptic regulation, which is fundamental to behavioral adaptation to the environment. The synapses, as functional units of cognition, represent major evolutionary targets. Consistently, fine synaptic tuning occurs at several levels, involving a novel class of molecular regulators known as long non-coding RNAs (lncRNAs). Non-coding RNAs operate mainly in mammals as epigenetic modifiers and enhancers of proteome diversity. The prominent evolutionary expansion of the gene number of lncRNAs in mammals, particularly in primates and humans, and their preferential neuronal expression does represent a driving force that enhanced the layering of synaptic control mechanisms. In the last few years, remarkable alterations of the expression of lncRNAs have been reported in psychiatric conditions such as schizophrenia, autism, and depression, suggesting unprecedented mechanistic insights into disruption of fine synaptic tuning underlying severe behavioral manifestations of psychosis. In this review, we integrate literature data from rodent pathological models and human evidence that proposes the biology of lncRNAs as a promising field of neuropsychiatric investigation

Re: "Antibiotic Exposure by 6 Months and Asthma and Allergy at 6 Years: Findings in a Cohort of 1,401 US Children"

n/

HUMAN MYOTONIC DYSTROPHIES: PROTEOME PROFILING AND DIFFERENTIATION STUDIES

Myotonic Dystrophy type 2 (DM2) is caused by a DNA microsatellite expansion within the ZNF9 gene leading to an abnormal splicing pattern largely responsible for the pathological condition. To better define the functional changes occurring in human DM2 myotubes, we performed a quantitative proteome comparison between myotubes of DM2 and control patients using two-dimensional gel electrophoresis followed by mass spectrometry. Our results indicate that the proteins, altered in DM2 cultures, belong to two major functional categories: i) mitochondrial components, with a reduction of Elongation factor Tu (EFTu), Heat Shock Protein 60 (HSP60), Glucose Regulated Protein 75 (GRP75) and Dienoyl-CoA-Isomerase, an enzyme involved in fatty acids degradation; ii) the ubiquitin proteasome system, with increase of the 26S proteasome regulatory subunit 13 and a reduction of Proteasome subunit Apha 6 and of Rad23B homolog. Altered ubiquitin-proteasomal activity is supported by a global reduction of cytosolic ubiquitinated proteins, nonetheless the accumulation of ubiquitin-protein conjugates after proteasomal inhibitor MG-132 treatment is maintained in DM2 and control cells, suggesting a higher degradation rate for the proteasome in myoblasts from patients affected by the disease. Although future work is required to clarify how these changes affect the protein degradation machinery and mitochondrial function and to evaluate if these changes also occur in the biopsies of DM2 patients, these results identify the mitochondrial proteins and the ubiquitin-proteasomal system as candidates potentially relevant to DM2 pathogenesis. Further analysis performed in Human skin fibroblasts primary cultures, obtained from patients biopsies, revealed an Hyperpolaryzation of the mitochondrial membrane potential involving DM2 cells, indicating a putative functional issue for mitochondria. As the evaluation of the Cytocrome c release following hydrogen peroxide treatment showed a differential response to this stress inducing compound, we pointed out a functional involvement of the DM2 mitochondrial-mediated cellular response to oxidative stress

THE IMPORTANT ROLE OF AKT IN THE MODULATION OF HEART INOTROPISM THROUGH L-TYPE CALCIUM CHANNELS FUNCTION

The insulin IGF1/Akt signaling pathway has recently been shown to be critical for the regulation of heart function and physiology. Indeed, compelling evidence shows activation of this pathway as one of the most important determinants for the enhancement of cardiac function and physiological growth in athletes, whereas its impairment is considered critical for the development of heart failure (HF). In this doctoral thesis, our aim was to determine the functional role of known and novel key-factors of this pathway to study whether their modulation might be envisaged as therapeutic tool for curing pathological cardiac hypertrophy (CH) and HF. Physiological CH is an adaptive response of the heart to stimuli, such as developmental growth and training and differs markedly from pathological hypertrophy occurring in patients with HF. In this thesis, we demonstrated the involvement of Akt kinase in regulating heart inotropism by modulating L-Type Ca2+ Channel (LTCC) density and function. In a mouse model with inducible and cardiac specific deletion of PDK1, the upstream activator of Akt, we found that the protein stability of the LTCC pore subunit (Cav\u3b11) can be modulated by the kinase. In particular, phosphorylation of the C-terminal coiled coil of the Cav\u3b22 chaperone subunit enhances LTCC protein stability by prevention of PEST-mediated Cav\u3b11 degradation. Subsequently, to determine whether the modulation of this mechanism may be used for the treatment of HF, we studied the fine-regulation of LTCC density and activity by investigating the functional role of Akt-phosphomimetics Cav\u3b22 constructs. Three Akt-phosphomimetic sequences corresponding to the Cav\u3b22 C-terminal coiled coil were identified and shown to protect Cav\u3b11 from protein degradation, through an increase in the number of functional LTCC. Moreover, to establish whether the Akt-dependent phosphorylation of CaV\u3b22 might be a trigger for the recruitment of other protein interacting partners, yeast two-hybrid screenings of human and mouse heart cDNA expression libraries revealed a fold-back interaction of the Akt-phosphorylated-Cav\u3b22 tail with a region of the Cav\u3b22 globular domain. Co-immunoprecipitation experiments confirmed this interaction, while negative results were obtained when Cav\u3b22-WT was used as bait. This provided the proof of concept for a mechanism of action that relies on Akt-dependent phosphorylation. Site-specific mutagenesis in the identified interacting domain confirmed this mechanism. All togheter, we found that the Akt-dependent protective effect on Cav\u3b11 stability might relay on Cav\u3b22 structural rearrangements, which follow the phosphorylated C-terminal coiled coil fold back on its globular domain. In conclusion, results from this doctoral thesis provide further insights into the role of the insulin IGF1/Akt signaling pathway and its role in the modulation of myocardial physiology and HF. These findings may lead to the development of new therapeutical tools that will be useful for the modulation of impaired cardiac contractility in HF

Bilateral neglected posterior dislocation of the shoulder treated by reverse arthroplasty and contralateral osteochondral autograft. A case report

Bilateral posterior dislocation of the glenohumeral joint is an uncommon event, that can be missed at the initial presentation. We report the case of a 76-year old woman, who suffered a traumatic bilateral posterior dislocation, that was diagnosed three months later. She underwent surgical treatment on both shoulders in a single stage. Since the right shoulder showed a defect of the articular surface >50%, a reverse shoulder arthroplasty was performed on this side. The resected portion of the humeral head was retrieved and used as osteochondral graft to fill the reverse Hill-Sachs lesion of the left shoulder. At 18-month follow up, the patient was pain-free and had recovered excellent shoulder function on both sides: Constant score was 79 for the right shoulder and 88 for the left one. X-rays showed a grade 1 scapular notch of the right reverse prosthesis and good incorporation of the graft in the left shoulder, with no evidence of degenerative joint changes. Neglected posterior dislocations of the shoulder can be surgically treated by replacement or reconstruction. In case of bilateral injuries, the surgeon should carefully evaluate the pathoanatomy of both glenohumeral joints in order to choose and plan the most suitable procedure. If shoulder replacement is required on one side, the resected portion of the humeral head can be used as osteochondral autograft for a reconstruction procedure in the opposite side. The choice is influenced by several variables and decision-making might be challenging

The future of long-acting cabotegravir plus rilpivirine therapy: deeds and misconceptions

HIV infection is currently managed as a chronic disease because of improvements in antiretroviral therapy (ART). Switching to a new regimen is a natural event during long-term therapy to avoid problems related to toxicity, adherence, failure, and potential selection of drug resistance. The development of co-formulations of multiple agents in one pill, and novel drug classes and drugs with a high genetic barrier to resistance have been important in this context. The approval of the long-acting, once-monthly or bimonthly injectable combination of the second-generation strand transfer integrase inhibitor (InSTI), cabotegravir (CAB) together with the non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (RPV) represents the most recent achievement in the search for potent and convenient ART. Several pivotal trials (such as LATTE-2, ATLAS, FLAIR, and ATLAS-2M) showed the high efficacy and safety of this long-acting formulation used as an induction-maintenance strategy. Few confirmed virological failures (CVF) have been observed. The combination of at least two of the following baseline factors, HIV-1 subtype A6/A1, a body mass index (BMI) ≥30 kg/m2, and RPV resistance-associated mutations, was associated with an increased risk of CVF at week 48. The data indicate that this long-acting therapeutic strategy is attractive and potent; therefore, defining the most appropriate patient for this treatment and how to handle practical issues is warranted