Temperature-Dependent Order-Disorder Phenomena in Crystal Structures Containing Dimers of Carboxylic Acids: The Crystal and Molecular Structure of 3,5-Dinitrobenzoic Acid at Room and Liquid Nitrogen Temperature and Statistics of the Geometries of Hydrogen-Bonded Carboxyl Groups

3,5-dinitrobenzoic acid crystallizes in space group P2i/c with four molecules in the unit cell. At room temperature (RT), the cell dimensions are a = 10.0237(4), b = 8.8728(3), c = 9.5090(4) A, = 95.68(1)° and V = 841.56(6) A3 and at liquid nitrogen temperature (LNT) a = 9.761(2), b = 8.9192(4), c = 9.444(2) A, /S = 97.55(1)° and V = 815.1(2) A3. At both temperatures, the crystals contain the common centrosymmetric carboxylic acid dimers. At RT the carboxyl groups are partially disordered, as indicated by the C=0 [1.249(3)] and C-0 [1.276(2)A] distances, C-C = 0 [118.4(2)1 and C-C-0 [116.4(2)°] angles and by the presence of disordered H atoms with occupancy factors of 0.63 and 0.37 in the O—O hydrogen bond. At LNT, the acidic proton is ordered with a distance of 0.96(2) A from the donor hydroxyl O atom and the carboxyl group geometry is normal, with C=0 1.232(2) and C-0 1.305(2) A and C-C = 0 120.6(1) and C-C-O 114.4(1)°. The differences Ar distances and A of the C-C-O angles are 0.027 A and 2.0°, respectively, at RT and 0.073 A and 6.2°, respectively, at LNT, which indicates an increase of ordering with decreasing temperature. The mechanism of disordering most probably invokes a temperature-dependent concerted two-proton jump across the dimer hydrogen bonds. To test the relationship between Ar and A, a statistical analysis is performed on the C-0 distances and C-C-O angles of RT and LNT dimer and non-dimer structures retrieved from the Cambridge Structural Database. The analysis indicates that disorder in RT dimers is more frequent than in RT non-dimers and also that ordering is pronounced in both LT dimer and non-dimer structures

24hour heart rate variability in shift workers: Impact of shift schedule

Abstract: 24-Hour Heart Rate Variability in Shift Workers: Impact of Shift Schedule: L.G.P.M. van AMELSVOORT, et al. Department of Epidemiology, Maastricht University-Disturbance of the circadian pattern of cardiac autonomic control by working at night when the physiological system anticipates rest could explain part of the elevated cardiovascular risk in shift workers. Analysis of Heart Rate Variability (HRV) is a non-invasive tool to estimate disturbances of the cardiac autonomic control. To assess the influence of working at night on cardiac autonomic control, HRV levels were determined in shift workers. 24-h ECG recordings were made during a day on morning shift and a day on night shift. Within person differences between a morning and a night shift were calculated. Possible modification of the reported effects by the shift schedule was determined. Significantly elevated mean %LF during sleep was found on a day worked on night shift compared with a day on day shift (%LF + 3.04, P<0.01). Type of shift schedule was found to be a significant modifier of this effect. The difference in %LF between the night and day shift for the different shift schedules apart were: + 0.88% for the workers in the fast forward rotating shift, + 3.06% for the fast backward rotating shift, + 6.15% (P<0.001) for the medium speed backward rotating shift and + 1.18% for the shift workers without a regular shift schedule. The results suggest an increased sympathetic dominance during a night shift sleep, indicating an inferior sleep quality. Optimisation of this schedule might diminish this impact and could contribute to a reduction of the cardiovascular disease risk among shift workers. (J Occup Health 2001; 43: 32-38

Structure of Complement Component C2a: Implications for Convertase Formation and Substrate Binding

SummaryC2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix α7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to “inside-out” signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix α7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases

Multifaceted Activities of Seven Nanobodies against Complement C4b

Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama (Lama glama) immunization, that bind to human C4b (Homo sapiens) with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined singleparticle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Functional treatment versus plaster for simple elbow dislocations (FuncSiE): a randomized trial

Background. Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures. After reduction of a simple dislocation, treatment options include immobilization in a static plaster for different periods of time or so-called functional treatment. Functional treatment is characterized by early active motion within the limits of pain with or without the use of a sling or hinged brace. Theoretically, functional treatment should prevent stiffness without introducing increased joint instability. The primary aim of this randomized controlled trial is to compare early functional treatment versus plaster immobilization following simple dislocations of the elbow. Methods/Design. The design of the study will be a multicenter randomized controlled trial of 100 patients who have sustained a simple elbow dislocation. After reduction of the dislocation, patients are randomized between a pressure bandage for 5-7 days and early functional treatment or a plaster in 90 degrees flexion, neutral position for pro-supination for a period of three weeks. In the functional group, treatment is started with early active motion within the limits of pain. Function, pain, and radiographic recovery will be evaluated at regular intervals over the subsequent 12 months. The primary outcome measure is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford elbow score, pain level at both sides, range of motion of the elbow joint at both sides, rate of secondary interventions and complication rates in both groups (secondary dislocation, instability, relaxation), health-related quality of life (Short-Form 36 and EuroQol-5D), radiographic appearance of the elbow joint (degenerative changes and heterotopic ossifications), costs, and cost-effectiveness. Discussion. The successful completion of this trial will provide evidence on the effectiveness of a functional treatment for the management of simple elbow dislocations. Trial Registration. The trial is registered at the Netherlands Trial Register (NTR2025)

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12

Temperature-Dependent Order-Disorder Phenomena in Crystal Structures Containing Dimers of Carboxylic Acids: The Crystal and Molecular Structure of 3,5-Dinitrobenzoic Acid at Room and Liquid Nitrogen Temperature and Statistics of the Geometries of Hydrogen-Bonded Carboxyl Groups

3,5-dinitrobenzoic acid crystallizes in space group P2i/c with four molecules in the unit cell. At room temperature (RT), the cell dimensions are a = 10.0237(4), b = 8.8728(3), c = 9.5090(4) A, = 95.68(1)° and V = 841.56(6) A3 and at liquid nitrogen temperature (LNT) a = 9.761(2), b = 8.9192(4), c = 9.444(2) A, /S = 97.55(1)° and V = 815.1(2) A3. At both temperatures, the crystals contain the common centrosymmetric carboxylic acid dimers. At RT the carboxyl groups are partially disordered, as indicated by the C=0 [1.249(3)] and C-0 [1.276(2)A] distances, C-C = 0 [118.4(2)1 and C-C-0 [116.4(2)°] angles and by the presence of disordered H atoms with occupancy factors of 0.63 and 0.37 in the O—O hydrogen bond. At LNT, the acidic proton is ordered with a distance of 0.96(2) A from the donor hydroxyl O atom and the carboxyl group geometry is normal, with C=0 1.232(2) and C-0 1.305(2) A and C-C = 0 120.6(1) and C-C-O 114.4(1)°. The differences Ar distances and A of the C-C-O angles are 0.027 A and 2.0°, respectively, at RT and 0.073 A and 6.2°, respectively, at LNT, which indicates an increase of ordering with decreasing temperature. The mechanism of disordering most probably invokes a temperature-dependent concerted two-proton jump across the dimer hydrogen bonds. To test the relationship between Ar and A, a statistical analysis is performed on the C-0 distances and C-C-O angles of RT and LNT dimer and non-dimer structures retrieved from the Cambridge Structural Database. The analysis indicates that disorder in RT dimers is more frequent than in RT non-dimers and also that ordering is pronounced in both LT dimer and non-dimer structures