Computer simulation of protein systems

Ligand binding to dihydrofolate reductase (DHFR) is discussed. This is an extremely important enzyme, as it is the target of several drugs (inhibitors) which are used clinically as antibacterials, antiprotozoals and in cancer chemotherapy. DHFR catalyzes the NADPH (reduced nicotinamide adenine dinucleotide phosphate) dependent reduction of dihydrofolate to tetrahydrofolate, which is used in several pathways of purine and pyrimidine iosynthesis, including that of thymidylate. Since DNA synthesis is dependent on a continuing supply of thymidylate, a blockade of DHFR resulting in a depletion of thymidylate can lead to the cessation of growth of a rapidly proliferating cell line. DHFR exhibits a significant species to species variability in its sensitivity to various inhibitors. For example, trimethoprim, an inhibitor of DHFR, binds to bacterial DHFR's 5 orders of magnitude greater than to vertebrate DHFR's. The structural mechanics, dynamics and energetics of a family of dihydrofolate reductases are studied to rationalize the basis for the inhibitor of these enyzmes and to understand the molecular basis of the difference in the binding constants between the species. This involves investigating the conformational changes induced in the protein on binding the ligand, the internal strain imposed by the enzyme on the ligand, the restriction of fluctuations in atom positions due to binding and the consequent change in entropy

Consequential life cycle assessment of biogas, biofuel and biomass energy options within an arable crop rotation

Feed in tariffs (FiTs) and renewable heat incentives (RHIs) are driving a rapid expansion in anaerobic digestion (AD) coupled with combined heat and power (CHP) plants in the UK. Farm models were combined with consequential life cycle assessment (CLCA) to assess the net environmental balance of representative biogas, biofuel and biomass scenarios on a large arable farm, capturing crop rotation and digestate nutrient cycling effects. All bioenergy options led to avoided fossil resource depletion. Global warming potential (GWP) balances ranged from -1732kgCO(2)eMg(-1) dry matter (DM) for pig slurry AD feedstock after accounting for avoided slurry storage to +2251kgCO(2)eMg(-1) DM for oilseed rape biodiesel feedstock after attributing indirect land use change (iLUC) to displaced food production. Maize monoculture for AD led to net GWP increases via iLUC, but optimized integration of maize into an arable rotation resulted in negligible food crop displacement and iLUC. However, even under best-case assumptions such as full use of heat output from AD-CHP, crop-biogas achieved low GWP reductions per hectare compared with Miscanthus heating pellets under default estimates of iLUC. Ecosystem services (ES) assessment highlighted soil and water quality risks for maize cultivation. All bioenergy crop options led to net increases in eutrophication after displaced food production was accounted for. The environmental balance of AD is sensitive to design and management factors such as digestate storage and application techniques, which are not well regulated in the UK. Currently, FiT payments are not dependent on compliance with sustainability criteria. We conclude that CLCA and ES effects should be integrated into sustainability criteria for FiTs and RHIs, to direct public money towards resource-efficient renewable energy options that achieve genuine climate protection without degrading soil, air or water qualit

A robust nanoscale experimental quantification of fracture energy in a bilayer material system

Accurate measurement of interfacial properties is critical any time two materials are bonded—in composites, tooth crowns, or when biomaterials are attached to the human body. Yet, in spite of this importance, reliable methods to measure interfacial properties between dissimilar materials remain elusive. Here we present an experimental approach to quantify the interfacial fracture energy Γ[subscript i] that also provides unique mechanistic insight into the interfacial debonding mechanism at the nanoscale. This approach involves deposition of an additional chromium layer (superlayer) onto a bonded system, where interface debonding is initiated by the residual tensile stress in the superlayer, and where the interface can be separated in a controlled manner and captured in situ. Contrary to earlier methods, our approach allows the entire bonded system to remain in an elastic range during the debonding process, such that Γ[subscript i] can be measured accurately. We validate the method by showing that moisture has a degrading effect on the bonding between epoxy and silica, a technologically important interface. Combining in situ through scanning electron microscope images with molecular simulation, we find that the interfacial debonding mechanism is hierarchical in nature, which is initiated by the detachment of polymer chains, and that the three-dimensional covalent network of the epoxy-based polymer may directly influence water accumulation, leading to the reduction of Γ[subscript i] under presence of moisture. The results may enable us to design more durable concrete composites that could be used to innovate transportation systems, create more durable buildings and bridges, and build resilient infrastructure.National Science Foundation (U.S.) (Grant CMS-0856325

Mathematically Gifted Adolescents Have Deficiencies in Social Valuation and Mentalization

Many mathematically gifted adolescents are characterized as being indolent, underachieving and unsuccessful despite their high cognitive ability. This is often due to difficulties with social and emotional development. However, research on social and emotional interactions in gifted adolescents has been limited. The purpose of this study was to observe differences in complex social strategic behaviors between gifted and average adolescents of the same age using the repeated Ultimatum Game. Twenty-two gifted adolescents and 24 average adolescents participated in the Ultimatum Game. Two adolescents participate in the game, one as a proposer and the other as a responder. Because of its simplicity, the Ultimatum Game is an apt tool for investigating complex human emotional and cognitive decision-making in an empirical setting. We observed strategic but socially impaired offers from gifted proposers and lower acceptance rates from gifted responders, resulting in lower total earnings in the Ultimatum Game. Thus, our results indicate that mathematically gifted adolescents have deficiencies in social valuation and mentalization

Publisher Correction: FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells.

The originally published version of this Article contained an error in Figure 2. In panel e, the blue bar was incorrectly labelled 'KRT8(+)/TOMATO(-)'. Furthermore, during the process of preparing a correction, the publication date of the Article was inadvertently changed to June 20th 2018. Both of these errors have been corrected in the PDF and HTML versions of the Article

FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells

Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.Peer reviewe

Corneal Replication Is an Interferon Response-Independent Bottleneck for Virulence of Herpes Simplex Virus 1 in the Absence of Virion Host Shutoff

Herpes simplex viruses lacking the virion host shutoff function (Δvhs) are avirulent and hypersensitive to type I and type II interferon (IFN). In this study, we demonstrate that even in the absence of IFN responses in AG129 (IFN-αβγR−/−) mice, Δvhs remains highly attenuated via corneal infection but is fully virulent via intracranial infection. The data demonstrate that the interferon-independent inherent replication defect of Δvhs has a significant impact upon peripheral replication and neuroinvasion

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function

Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation

. This work was supported by funding from NIH NICHHD (R01HD078592 to V.H.), NIH NICHHD (1K23HD073351 to A.D.), and a Junior Research grant by the Medical Faculty of the University of Leipzig (to D.R.). M.T.D. receives funding from the Great Ormond Street Hospital Children’s Charity (GOSHCC)

International Consensus Guideline on Small for Gestational Age (SGA): Etiology and Management from Infancy to Early Adulthood

: This International Consensus Guideline was developed by experts in the field of SGA of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Besides, it presents long-term consequences of SGA birth and new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, and the metabolic and cardiovascular health of young adults born SGA after cessation of childhood-GH-treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardio-metabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at age of 3-4 years, should be referred for diagnostic work-up. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033-0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3-4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle