Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles

Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in ω (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low ω global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes

Physics and Applications of Laser Diode Chaos

An overview of chaos in laser diodes is provided which surveys experimental achievements in the area and explains the theory behind the phenomenon. The fundamental physics underpinning this behaviour and also the opportunities for harnessing laser diode chaos for potential applications are discussed. The availability and ease of operation of laser diodes, in a wide range of configurations, make them a convenient test-bed for exploring basic aspects of nonlinear and chaotic dynamics. It also makes them attractive for practical tasks, such as chaos-based secure communications and random number generation. Avenues for future research and development of chaotic laser diodes are also identified.Comment: Published in Nature Photonic

Visualization of Early Events in Acetic Acid Denaturation of HIV-1 Protease: A Molecular Dynamics Study

Protein denaturation plays a crucial role in cellular processes. In this study, denaturation of HIV-1 Protease (PR) was investigated by all-atom MD simulations in explicit solvent. The PR dimer and monomer were simulated separately in 9 M acetic acid (9 M AcOH) solution and water to study the denaturation process of PR in acetic acid environment. Direct visualization of the denaturation dynamics that is readily available from such simulations has been presented. Our simulations in 9 M AcOH reveal that the PR denaturation begins by separation of dimer into intact monomers and it is only after this separation that the monomer units start denaturing. The denaturation of the monomers is flagged off by the loss of crucial interactions between the α-helix at C-terminal and surrounding β-strands. This causes the structure to transit from the equilibrium dynamics to random non-equilibrating dynamics. Residence time calculations indicate that denaturation occurs via direct interaction of the acetic acid molecules with certain regions of the protein in 9 M AcOH. All these observations have helped to decipher a picture of the early events in acetic acid denaturation of PR and have illustrated that the α-helix and the β-sheet at the C-terminus of a native and functional PR dimer should maintain both the stability and the function of the enzyme and thus present newer targets for blocking PR function

Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling

Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones

The importance of psychological factors in pediatric recurrent headaches

Background: Headache is one of the most common health problems of children and adolescents. At least 10% of pediatric population suffer from recurrent headaches without underlying organic/structural etiologies. Social stressors such as conflicts in the family, parental divorce, death/illness of a family member, poor relationships with peers, as well as problems related to school have impact on the occurrence of nonorganic headaches. The aim: of this paper was to determine characteristics of recurrent headaches, psychological, cognitive and emotional factors that can provoke or aggravate somatic problems, and psychological characteristics of pediatric patients with episodic headaches. Material and methods: This retrospective study included children and adolescents with nonorganic recurrent headaches sent to psychological evaluation during the period from January 1, 2014 till December 31,2016. Results: The study cohort comprised 101 patients (40 males and 61 females) aged 12.24 ± 2.71 (range 7-18) years who experienced headaches at least once a week. One third lived in dysfunctional and broken families, 29% had poor relations with peers, and 20% had problems related to school. Difficulties in copying with stress were found in ¼ of patients. Conclusion: Psychological evaluation is important tool for determination psychosocial stressors and nonorganic comorbidities of migraine and tension-type headache, as well as for diagnosis of secondary headaches attributed to psychiatric disorders

Treatments costs associated with inpatient clinical deterioration

Aims: This study aimed to quantify the health economic treatment costs of clinical deterioration of patients within 72 h of admission via the emergency department. Methods: This study was conducted between March 2018 and February 2019 in two hospitals in regional New South Wales, Australia. All patients admitted via the emergency department were screened for clinical deterioration (defined as initiation of a medical emergency team call, cardiac arrest or unplanned admission to Intensive Care Unit) within 72 h through the site clinical deterioration databases. Patient characteristics, including pre-existing conditions, diagnosis and administrative data were collected. Results: 1600 patients clinically deteriorated within 72 h of hospital admission. Linked treatment cost data were available for 929 (58%) of these patients across 352 Australian Refined Diagnosis Related Groups. The average (standard deviation) treatment costs for patients who deteriorated within 72 h was $26,778 ($34,007) compared to $7727 ($12,547). The average hospital length of stay of the deterioration group was nearly 8 days longer than patients without deterioration. When controlling for length of stay and Australian Refined Diagnosis Related Group codes, the incremental cost per episode of deterioration was $14,134. Conclusion: Clinical deterioration within 72 h of admission is associated with increased treatment costs irrespective of diagnosis, hospital length of stay and age. Implementation of interventions known to prevent patient deterioration require evaluation