Neural model of dopaminergic control of arm movements in Parkinson’s disease bradykinesia

Patients suffering from Parkinson’s disease display a number of symptoms such a resting tremor, bradykinesia, etc. Bradykinesia is the hallmark and most disabling symptom of Parkinson’s disease (PD). Herein, a basal ganglia-cortico-spinal circuit for the control of voluntary arm movements in PD bradykinesia is extended by incorporating DAergic innervation of cells in the cortical and spinal components of the circuit. The resultant model simulates successfully several of the main reported effects of DA depletion on neuronal, electromyographic and movement parameters of PD bradykinesia

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): Exome sequencing of trios, monozygotic twins and tumours

BACKGROUND: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. METHODS: We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons. RESULTS: The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations. CONCLUSIONS: Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users

Neutron charge form factor at large q2q^2

The neutron charge form factor $G_{En}(q)$ is determined from an analysis of the deuteron quadrupole form factor $F_{C2}$ data. Recent calculations, based on a variety of different model interactions and currents, indicate that the contributions associated with the uncertain two-body operators of shorter range are relatively small for $F_{C2}$, even at large momentum transfer $q$. Hence, $G_{En}(q)$ can be extracted from $F_{C2}$ at large $q^2$ without undue systematic uncertainties from theory.Comment: 8 pages, 3 figure

Effective interaction between helical bio-molecules

The effective interaction between two parallel strands of helical bio-molecules, such as deoxyribose nucleic acids (DNA), is calculated using computer simulations of the "primitive" model of electrolytes. In particular we study a simple model for B-DNA incorporating explicitly its charge pattern as a double-helix structure. The effective force and the effective torque exerted onto the molecules depend on the central distance and on the relative orientation. The contributions of nonlinear screening by monovalent counterions to these forces and torques are analyzed and calculated for different salt concentrations. As a result, we find that the sign of the force depends sensitively on the relative orientation. For intermolecular distances smaller than $6\AA$ it can be both attractive and repulsive. Furthermore we report a nonmonotonic behaviour of the effective force for increasing salt concentration. Both features cannot be described within linear screening theories. For large distances, on the other hand, the results agree with linear screening theories provided the charge of the bio-molecules is suitably renormalized.Comment: 18 pages, 18 figures included in text, 100 bibliog

Reorientation-effect measurement of the first 2+ state in 12C : Confirmation of oblate deformation

A Coulomb-excitation reorientation-effect measurement using the TIGRESS γ−ray spectrometer at the TRIUMF/ISAC II facility has permitted the determination of the 〈21 +‖E2ˆ‖21 +〉 diagonal matrix element in 12C from particle−γ coincidence data and state-of-the-art no-core shell model calculations of the nuclear polarizability. The nuclear polarizability for the ground and first-excited (21 +) states in 12C have been calculated using chiral NN N4LO500 and NN+3NF350 interactions, which show convergence and agreement with photo-absorption cross-section data. Predictions show a change in the nuclear polarizability with a substantial increase between the ground state and first excited 21 + state at 4.439 MeV. The polarizability of the 21 + state is introduced into the current and previous Coulomb-excitation reorientation-effect analyses of 12C. Spectroscopic quadrupole moments of QS(21 +)=+0.053(44) eb and QS(21 +)=+0.08(3) eb are determined, respectively, yielding a weighted average of QS(21 +)=+0.071(25) eb, in agreement with recent ab initio calculations. The present measurement confirms that the 21 + state of 12C is oblate and emphasizes the important role played by the nuclear polarizability in Coulomb-excitation studies of light nuclei

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease