CrossCheck:toward passive sensing and detection of mental health changes in people with schizophrenia

Early detection of mental health changes in individuals with serious mental illness is critical for effective intervention. CrossCheck is the first step towards the passive monitoring of mental health indicators in patients with schizophrenia and paves the way towards relapse prediction and early intervention. In this paper, we present initial results from an ongoing randomized control trial, where passive smartphone sensor data is collected from 21 outpatients with schizophrenia recently discharged from hospital over a period ranging from 2-8.5 months. Our results indicate that there are statistically significant associations between automatically tracked behavioral features related to sleep, mobility, conversations, smartphone usage and self-reported indicators of mental health in schizophrenia. Using these features we build inference models capable of accurately predicting aggregated scores of mental health indicators in schizophrenia with a mean error of 7.6% of the score range. Finally, we discuss results on the level of personalization that is needed to account for the known variations within people. We show that by leveraging knowledge from a population with schizophrenia, it is possible to train accurate personalized models that require fewer individual-specific data to quickly adapt to new user

Understanding and addressing mathematics anxiety using perspectives from education, psychology and neuroscience

Mathematics anxiety is a significant barrier to mathematical learning. In this article, we propose that state or on-task mathematics anxiety impacts on performance, while trait mathematics anxiety leads to the avoidance of courses and careers involving mathematics. We also demonstrate that integrating perspectives from education, psychology and neuroscience contributes to a greater understanding of mathematics anxiety in its state and trait forms. Research from cognitive psychology and neuroscience illustrates the effect of state mathematics anxiety on performance and research from cognitive, social and clinical psychology, and education can be used to conceptualise the origins of trait mathematics anxiety and its impact on avoidant behaviour. We also show that using this transdisciplinary framework to consider state and trait mathematics anxiety separately makes it possible to identify strategies to reduce the negative effects of mathematics anxiety. Implementation of these strategies among particularly vulnerable groups, such as pre-service teachers, could be beneficial

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T > C p.Ile72Thr and c.380A > G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145 + 2 T > C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be ategorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification

FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded

An easy-to-use, versatile and freely available graphic web server, FoldIndex is described: it predicts if a given protein sequence is intrinsically unfolded implementing the algorithm of Uversky and co-workers, which is based on the average residue hydrophobicity and net charge of the sequence. FoldIndex has an error rate comparable to that of more sophisticated fold prediction methods. Sliding windows permit identification of large regions within a protein that possess folding propensities different from those of the whole protein

The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction

Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment

Building Bridges Between the Clinic and the Laboratory: A Meeting Review – Brain Malformations: A Roadmap for Future Research

In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.The corrigendum to this article is in ORE: http://hdl.handle.net/10871/33588Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.D.M.E. and J.K. are supported by the Office of Naval Research (ONR) Grant N000141410538. M.S. is supported by the BBSRC (BB/K006231/1), a Wellcome Trust Institutional Strategic Support Award (WT097835MF, WT105618MA), and a Marie Curie Initial Training Network (ITN) action PerFuMe (316723). M.C.V.M., J.S., H.P., C.F., T.V. and W.A.G. are supported by the NGHRI Intramural Research Program. G.R. is supported by the Kahn Family Foundation and the Israeli Centers of Excellence (I-CORE) Program (ISF grant no. 41/11)

Nanoparticle display of neuraminidase elicits enhanced antibody responses and protection against influenza A virus challenge

Current Influenza virus vaccines primarily induce antibody responses against variable epitopes in hemagglutinin (HA), necessitating frequent updates. However, antibodies against neuraminidase (NA) can also confer protection against influenza, making NA an attractive target for the development of novel vaccines. In this study, we aimed to enhance the immunogenicity of recombinant NA antigens by presenting them multivalently on a nanoparticle carrier. Soluble tetrameric NA antigens of the N1 and N2 subtypes, confirmed to be correctly folded by cryo-electron microscopy structural analysis, were conjugated to Mi3 self-assembling protein nanoparticles using the SpyTag-SpyCatcher system. Immunization of mice with NA-Mi3 nanoparticles induced higher titers of NA-binding and -inhibiting antibodies and improved protection against a lethal challenge compared to unconjugated NA. Additionally, we explored the co-presentation of N1 and N2 antigens on the same Mi3 particles to create a mosaic vaccine candidate. These mosaic nanoparticles elicited antibody titers that were similar or superior to the homotypic nanoparticles and effectively protected against H1N1 and H3N2 challenge viruses. The NA-Mi3 nanoparticles represent a promising vaccine candidate that could complement HA-directed approaches for enhanced potency and broadened protection against influenza A virus