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This article, published in the journal Neuropediatrics, discusses the use of MRI imaging in 10 children with enterovirus-associated acute flaccid myelitis (AFM). AFM is characterized by limb weakness, decreased muscle tone, and cranial nerve involvement, and is predominantly caused by enterovirus infections. The MRI findings in these patients showed longitudinal spinal cord lesions mainly affecting the gray matter, as well as lesions in the brainstem and cerebellum. Supratentorial involvement was uncommon. The study confirms previous findings about the MRI imaging findings in enterovirus-associated AFM. [Extracted from the article] more...

A seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol -1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases., (open access.) more...

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures., (open access.) more...

Competing Interests: None declared. Views expressed are solely those of the authors and do not represent official positions of their institutions or committees with which they are affiliated.

Elizabethkingia anophelis is a multidrug-resistant pathogen causing high mortality and morbidity in adults with comorbidities and neonates. We report a Dutch case of E. anophelis meningitis in a neonate, clonally related to samples taken from an automated infant milk dispenser located at the family's residence. We inform about the emergence of E. anophelis and suggest molecular surveillance in hospitals and other health settings. This is the first case connecting an automated formula dispenser to an invasive infection in a neonate. more...

Objectives: To describe the use and outcomes of the neurological wake-up test (NWT) in pediatric severe traumatic brain injury (pTBI)., Design: Retrospective single-center observational cohort study., Setting: Medical-surgical tertiary pediatric intensive care unit (PICU) in a university medical center and Level 1 Trauma Center., Patients: Children younger than 18 years with severe TBI [i.e., Glasgow Coma Scale (GCS) of ≤8] admitted between January 2010 and December 2020. Subjects with non-traumatic brain injury were excluded., Measurements and Main Results: Of 168 TBI patients admitted, 36 (21%) met the inclusion criteria. Median age was 8.5 years [2 months to 16 years], 5 patients were younger than 6 months. Median initial Glasgow Coma Scale (GCS) and Glasgow Motor Scale (GMS) was 6 [3-8] and 3 [1-5]. NWTs were initiated in 14 (39%) patients, with 7 (50%) labelled as successful. Fall from a height was the underlying injury mechanism in those seven. NWT-failure occurred in patients admitted after traffic accidents. Sedation use in both NWT-subgroups (successful vs. failure) was comparable. Cause of NWT-failure was non-arousal (71%) or severe agitation (29%). Subjects with NWT failure subsequently had radiological examination (29%), repeat NWT (43%), continuous interruption of sedation (14%) or intracranial pressure (ICP) monitoring (14%). The primary reason for not doing NWTs was intracranial hypertension in 59%. Compared to the NWT-group, the non-NWT group had a higher PRISM III score (18.9 vs. 10.6), lower GCS/GMS at discharge, more associated trauma, and circulatory support. Nine patients (25%) died during their PICU admission, none of them had an NWT., Conclusion: We observed limited use of NWTs in pediatric severe TBI. Patients who failed the NWT were indistinguishable from those without NWT. Both groups were more severely affected compared to the NWT successes. Therefore, our results may indicate that only a select group of severe pTBI patients qualify for the NWT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Mulder, Helfferich and Kneyber.) more...

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form 1 . In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations 2-4 . Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid-solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1-2 kJ mol -1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control 5 ., (© 2023. The Author(s).) more...

Background and Purpose: Acute flaccid myelitis (AFM) and transverse myelitis (TM) are serious conditions that may be difficult to differentiate, especially at onset of disease. In this study, we compared clinical features of pediatric AFM and TM and evaluated current diagnostic criteria, aiming to improve early and accurate diagnosis., Methods: Two cohorts of children with enterovirus D68-associated AFM and clinically diagnosed TM were compared regarding presenting clinical features, additional investigations, and outcome. Current diagnostic criteria for AFM and TM were applied to evaluate their specificity., Results: Children with AFM (n = 21) compared to those with TM (n = 36) were younger (median 3 vs. 10 years), more often had a prodromal illness (100% vs. 39%), predominant proximal weakness (69% vs. 17%), and hyporeflexia (100% vs. 44%), and less often had sensory deficits (0% vs. 81%), bowel and/or bladder dysfunction (12% vs. 69%), and hyperreflexia (0% vs. 44%). On magnetic resonance imaging, brainstem involvement was more common in AFM (74% vs. 21%), whereas supratentorial abnormalities were only seen in TM (0% vs. 40%). When omitting the criterion of a sensory level, 11 of 15 (73%) children with AFM fulfilled the diagnostic criteria for TM. Of children with TM, four of 33 (12%) fulfilled the diagnostic criteria for probable/definite AFM., Conclusions: Although there is considerable overlap between AFM and TM in children, we found important early differentiating clinical and diagnostic features. Meeting diagnostic criteria for AFM in children with TM and vice versa underlines the importance of thorough clinical examination and early and accurate diagnostic studies., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.) more...

Background: Acute flaccid paralysis (AFP) is characterized by rapidly progressive limb weakness with low muscle tone. It has a broad differential diagnosis, which includes acute flaccid myelitis (AFM), a rare polio-like condition that mainly affects young children. Differentiation between AFM and other causes of AFP may be difficult, particularly at onset of disease. Here, we evaluate the diagnostic criteria for AFM and compare AFM to other causes of acute weakness in children, aiming to identify differentiating clinical and diagnostic features., Methods: The diagnostic criteria for AFM were applied to a cohort of children with acute onset of limb weakness. An initial classification based on positive diagnostic criteria was compared to the final classification, based on application of features suggestive for an alternative diagnosis and discussion with expert neurologists. Cases classified as definite, probable, or possible AFM or uncertain, were compared to cases with an alternative diagnosis., Results: Of 141 patients, seven out of nine patients initially classified as definite AFM, retained this label after further classification. For probable AFM, this was 3/11, for possible AFM 3/14 and for uncertain 11/43. Patients initially classified as probable or possible AFM were most commonly diagnosed with transverse myelitis (16/25). If the initial classification was uncertain, Guillain-Barré syndrome was the most common diagnosis (31/43). Clinical and diagnostic features not included in the diagnostic criteria, were often used for the final classification., Conclusion: The current diagnostic criteria for AFM usually perform well, but additional features are sometimes required to distinguish AFM from other conditions., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, relevant to this study., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.) more...

BackgroundAcute flaccid myelitis (AFM) is a polio-like condition affecting mainly children and involving the central nervous system (CNS). AFM has been associated with different non-polio-enteroviruses (EVs), in particular EV-D68 and EV-A71. Reliable incidence rates in European countries are not available.AimTo report AFM incidence in children in the Netherlands and its occurrence relative to EV-D68 and EV-A71 detections.MethodsIn 10 Dutch hospitals, we reviewed electronic health records of patients diagnosed with a clinical syndrome including limb weakness and/or CNS infection and who were < 18 years old when symptoms started. After excluding those with a clear alternative diagnosis to AFM, those without weakness, and removing duplicate records, only patients diagnosed in January 2014-December 2019 were retained and further classified according to current diagnostic criteria. Incidence rates were based on definite and probable AFM cases. Cases' occurrences during the study period were co-examined with laboratory-surveillance detections of EV-D68 and EV-A71.ResultsAmong 143 patients included, eight were classified as definite and three as probable AFM. AFM mean incidence rate was 0.06/100,000 children/year (95% CI: -0.03 to 0.14). All patient samples were negative for EV-A71. Of respiratory samples in seven patients, five were EV-D68 positive. AFM cases clustered in periods with increased EV-D68 and EV-A71 detections.ConclusionsAFM is rare in children in the Netherlands. The temporal coincidence of EV-D68 circulation and AFM and the detection of this virus in several cases' samples support its association with AFM. Increased AFM awareness among clinicians, adequate diagnostics and case registration matter to monitor the incidence. more...

Crystal structure prediction (CSP) is generally used to complement experimental solid form screening and applied to individual molecules in drug development. The fast development of algorithms and computing resources offers the opportunity to use CSP earlier and for a broader range of applications in the drug design cycle. This study presents a novel paradigm of CSP specifically designed for structurally related molecules, referred to as Quick-CSP. The approach prioritizes more accurate physics through robust and transferable tailor-made force fields (TMFFs), such that significant efficiency gains are achieved through the reduction of expensive ab initio calculations. The accuracy of the TMFF is increased by the introduction of electrostatic multipoles, and the fragment-based force field parameterization scheme is demonstrated to be transferable for a family of chemically related molecules. The protocol is benchmarked with structurally related compounds from the Bromodomain and Extraterminal (BET) domain inhibitors series. A new convergence criterion is introduced that aims at performing only as many ab initio optimizations of crystal structures as required to locate the bottom of the crystal energy landscape within a user-defined accuracy. The overall approach provides significant cost savings ranging from three- to eight-fold less than the full-CSP workflow. The reported advancements expand the scope and utility of the underlying CSP building blocks as well as their novel reassembly to other applications earlier in the drug design cycle to guide molecule design and selection. more...

Objective: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM., Methods: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75)., Results: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02)., Conclusion: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.) more...

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population., (Copyright © 2021 Elsevier Ltd. All rights reserved.) more...

Acute flaccid myelitis is characterized by the combination of acute flaccid paralysis and a spinal cord lesion largely restricted to the gray matter on magnetic resonance imaging. The term acute flaccid myelitis was introduced in 2014 after the upsurge of pediatric cases in the USA with enterovirus D68 infection. Since then, an increasing number of cases have been reported worldwide. Whereas the terminology is new, the clinical syndrome has been recognized in the past in association with several other neurotropic viruses such as poliovirus.Conclusion: This review presents the current knowledge on acute flaccid myelitis with respect to the clinical presentation and its differential diagnosis with Guillain-Barré syndrome and acute transverse myelitis. We also discuss the association with enterovirus D68 and the presumed pathophysiological mechanism of this infection causing anterior horn cell damage. Sharing clinical knowledge and insights from basic research is needed to make progress in diagnosis, treatment, and prevention of this new polio-like disease. What is Known: • Acute flaccid myelitis (AFM) is a polio-like condition characterized by rapid progressive asymmetric weakness, together with specific findings on MRI • AFM has been related to different viral agents, but recent outbreaks are predominantly associated with enterovirus D68. What is New: • Improving knowledge on AFM must increase early recognition and adequate diagnostic procedures by clinicians. • The increasing incidence of AFM urges cooperation between pediatricians, neurologists, and microbiologists for the development of treatment and preventive options. more...

Room-temperature ionic liquids (ILs) are a unique, novel class of designer solvents and materials with exclusive properties, attracting substantial attention in fields like energy storage and supercapacitors as well as in ion-based signal processing and electronics. For most applications, ILs need to be incorporated or embedded in solid materials like porous hosts. We investigate the dynamic structure of ILs embedded in well-defined pores of metal-organic frameworks (MOFs). The experimental data combined with molecular dynamics simulations unveil astonishing dynamic properties of the IL in the MOF nanoconfinement. At low IL loadings, the ions drift in the pores along the electric field, whereas at high IL loadings, collective field-induced interactions of the cations and anions lead to blocking the transport, thus suppressing the ionic mobility and tremendously decreasing the conductivity. The mutual pore blockage causes immobilized ions in the pores, resulting in a highly inhomogeneous IL density and bunched-up ions at the clogged pores. These results provide novel molecular-level insights into the dynamics of ILs in nanoconfinement, significantly enhancing the tunability of IL material properties. more...

Background: Enterovirus-D68 (EV-D68) is a respiratory virus within the genus Enterovirus and the family of Picornaviridae. Genetically, it is closely related to rhinovirus that replicates in the respiratory tract and causes respiratory disease. Since 2014, EV-D68 has been associated with the neurologic syndrome of acute flaccid myelitis (AFM)., Methods: In October 2016, questionnaires were sent out to a European network including 66 virologists and clinicians, to develop an inventory of EV-D68-associated AFM cases in Europe. Clinical and virologic information of case patients was requested. In addition, epidemiologic information on EV testing was collected for the period between March and October 2016., Results: Twenty-nine cases of EV-D68-associated AFM were identified, from 12 different European countries. Five originated from France, 5 from Scotland and 3 each from Sweden, Norway and Spain. Twenty-six were children (median age 3.8 years), 3 were adults. EV-D68 was detected in respiratory materials (n = 27), feces (n = 8) and/or cerebrospinal fluid (n = 2). Common clinical features were asymmetric flaccid limb weakness, cranial nerve deficits and bulbar symptoms. On magnetic resonance imaging, typical findings were hyperintensity of the central cord and/or brainstem; low motor amplitudes with normal conduction velocities were seen on electromyography. Full clinical recovery was rare (n = 3), and 2 patients died. The epidemiologic data from 16 European laboratories showed that of all EV-D68-positive samples, 99% was detected in a respiratory specimen., Conclusions: For 2016, 29 EV-D68-related AFM cases were identified in mostly Western Europe. This is likely an underestimation, because case identification is dependent on awareness among clinicians, adequate viral diagnostics on respiratory samples and the capability of laboratories to type EVs. more...

Using ab initio and classical molecular dynamics simulations, we study pre-melting phenomena in pristine coincident-site-lattice grain boundaries (GBs) in proton-disordered hexagonal ice Ih at temperatures just below the melting point Tm. Concerning pre-melt-layer thicknesses, the results are consistent with the available experimental estimates for low-disorder impurity-free GBs. With regard to molecular mobility, the simulations provide a key new insight: the translational motion of the water molecules is found to be subdiffusive for time scales from ∼10 ns up to at least 0.1 μs. Moreover, the fact that the anomalous diffusion occurs even at temperatures just below Tm where the bulk supercooled liquid still diffuses normally suggests that it is related to the confinement of the GB pre-melt layers by the surrounding crystalline environment. Furthermore, we show that this behavior can be characterized by continuous-time random walk models in which the waiting-time distributions decay according to power-laws that are very similar to those describing dynamics in glass-forming systems. more...

Proton conducting nanoporous materials attract substantial attention with respect to applications in fuel cells, supercapacitors, chemical sensors, and information processing devices inspired by biological systems. Here, a crystalline, nanoporous material which offers dynamic remote-control over the proton conduction is presented. This is realized by using surface-mounted metal-organic frameworks (SURMOFs) with azobenzene side groups that can undergo light-induced reversible isomerization between the stable trans and cis states. The trans-cis photoisomerization results in the modulation of the interaction between MOF and guest molecules, 1,4-butanediol and 1,2,3-triazole; enabling the switching between the states with significantly increased (trans) and reduced (cis) conductivity. Quantum chemical calculations show that the trans-to-cis isomerization results in the formation of stronger hydrogen bridges of the guest molecules with the azo groups, causing stronger bonding of the guest molecules and, as a result, smaller proton conductivity. It is foreseen that photoswitchable proton-conducting materials may find its application in advanced, remote-controllable chemical sensors, and a variety of devices based on the conductivity of protons or other charged molecules, which can be interfaced with biological systems., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

Molecular simulation has emerged as an essential tool for modern-day research, but obtaining proper results and making reliable conclusions from simulations requires adequate sampling of the system under consideration. To this end, a variety of methods exist in the literature that can enhance sampling considerably, and increasingly sophisticated, effective algorithms continue to be developed at a rapid pace. Implementation of these techniques, however, can be challenging for experts and non-experts alike. There is a clear need for software that provides rapid, reliable, and easy access to a wide range of advanced sampling methods and that facilitates implementation of new techniques as they emerge. Here we present SSAGES, a publicly available Software Suite for Advanced General Ensemble Simulations designed to interface with multiple widely used molecular dynamics simulations packages. SSAGES allows facile application of a variety of enhanced sampling techniques-including adaptive biasing force, string methods, and forward flux sampling-that extract meaningful free energy and transition path data from all-atom and coarse-grained simulations. A noteworthy feature of SSAGES is a user-friendly framework that facilitates further development and implementation of new methods and collective variables. In this work, the use of SSAGES is illustrated in the context of simple representative applications involving distinct methods and different collective variables that are available in the current release of the suite. The code may be found at: https://github.com/MICCoM/SSAGES-public. more...

Background: Acute flaccid myelitis (AFM) is a relatively rare disorder affecting the anterior horn of the spinal cord and brain stem. It is characterised by rapid progressive weakness of the limbs and respiratory muscles, often combined with cranial nerve dysfunction. This used to be seen in infections with the polio virus, but in recent years, AFM has been mainly associated with enterovirus D68 infection., Case Description: A boy of nearly 4 years-old developed rapidly progressive weakness and respiratory failure after an upper airway infection. Initially, Guillain-Barré syndrome was suspected, but after further investigations enterovirus D68 was detected in the nasopharyngeal aspirate and the diagnosis of AFM was made., Conclusion: Progressive weakness after a respiratory tract infection should raise the suspicion of enterovirus-associated AFM. This syndrome can be distinguished from Guillain-Barré syndrome by its more rapid progression, asymmetrical weakness and greater involvement of the upper limbs. The diagnosis can be confirmed by typical findings on MRI and electromyography of the spinal cord and brain stem, combined with the detection of enterovirus D68 in nasopharyngeal specimens. more...

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment., (Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.) more...

Glasses produced via physical vapor deposition can display greater kinetic stability and lower enthalpy than glasses prepared by liquid cooling. While the reduced enthalpy has often been used as a measure of the stability, it is not obvious whether dynamic measures of stability provide the same view. Here, we study dynamics in vapor-deposited and liquid-cooled glass films using molecular simulations of a bead-spring polymer model as well as a Lennard-Jones binary mixture in two and three dimensions. We confirm that the dynamics in vapor-deposited glasses is indeed slower than in ordinary glasses. We further show that the inherent structure energy is a good reporter of local dynamics, and that aged systems and glasses prepared by cooling at progressively slower rates exhibit the same behavior as vapor-deposited materials when they both have the same inherent structure energy. These findings suggest that the stability inferred from measurements of the energy is also manifested in dynamic observables, and they strengthen the view that vapor deposition processes provide an effective strategy for creation of stable glasses. more...

On cooling toward the glass transition temperature, glass-forming liquids display long periods of localized motion interrupted by fast "jumps" in the single-particle trajectories. Several theoretical models based on these single-particle jumps have been proposed, most prominently the continuous-time random walk (CTRW). The central assumption of the CTRW is that jumps are renewal events, i.e. that the internal clock of a particle can be reset upon a jump. In this paper, I present an easy-to-implement method to test whether jumps detected in a supercooled liquid or glass are renewal events or not. The test was applied to molecular dynamics simulations of a short-chain polymer melt, demonstrating that the jumps can in fact be treated as renewal events. The test further revealed that additional relaxation processes are present which are not accounted for in the CTRW picture, highlighting the limitations of this approach. The notion of renewal events in glass-forming systems could be a very important building block for the interpretation of aging and the glass transition. Furthermore, it could have practical implications for the study of non-equilibrium dynamics in glasses as well as mechanical rejuvenation. more...

A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders. more...