One of the possible solutions to the world's rapidly increasing energy demand is the development of new photoelectrochemical cells with improved light absorption. This requires development of ...semiconductor materials which have appropriate bandgaps to absorb a large part of the solar spectrum at the same time as being stable in aqueous environments. Here we demonstrate an efficient, computational screening of relevant oxide and oxynitride materials based on electronic structure calculations resulting in the reduction of a vast space of 5400 different materials to only 15 promising candidates. The screening is based on an efficient and reliable way of calculating semiconductor band gaps. The outcome of the screening includes all already known successful materials of the types investigated plus some new ones which warrant further experimental investigation.
We describe the structural and kinematic properties of the first compact stellar systems discovered by the Archive of Intermediate Mass Stellar Systems project. These spectroscopically confirmed ...objects have sizes (∼6 < R
e pc < 500) and masses (∼2 × 106 < M
*/M⊙ < 6 × 109) spanning the range of massive globular clusters, ultracompact dwarfs (UCDs) and compact elliptical galaxies (cEs), completely filling the gap between star clusters and galaxies. Several objects are close analogues to the prototypical cE, M32. These objects, which are more massive than previously discovered UCDs of the same size, further call into question the existence of a tight mass–size trend for compact stellar systems, while simultaneously strengthening the case for a universal ‘zone of avoidance’ for dynamically hot stellar systems in the mass–size plane. Overall, we argue that there are two classes of compact stellar systems (1) massive star clusters and (2) a population closely related to galaxies. Our data provide indications for a further division of the galaxy-type UCD/cE population into two groups, one population that we associate with objects formed by the stripping of nucleated dwarf galaxies, and a second population that formed through the stripping of bulged galaxies or are lower mass analogues of classical ellipticals. We find compact stellar systems around galaxies in low- to high-density environments, demonstrating that the physical processes responsible for forming them do not only operate in the densest clusters.
Leukocyte immunoglobulin (Ig)‐like receptors (LILR) LILRB1 and LILRB2 may play a pivotal role in maintaining self‐tolerance and modulating the immune response through interaction with classical and ...nonclassical HLA molecules. Although both diversity and natural selection patterns over HLA genes have been extensively evaluated, little information is available concerning the genetic diversity and selection signatures on the LILRB1/2 regions. Therefore, we identified the LILRB1/2 genetic diversity using next‐generation sequencing in a population sample from São Paulo State, Brazil. We identified 58 LILRB1 Single Nucleotide Variants (SNVs), which gave rise to 13 haplotypes, and 41 LILRB2 SNVs arranged into 11 haplotypes. Although we may not exclude as a possible effect of population structure, we found evidence of either positive or purifying selection on LILRB1/2 coding regions. Some residues in both proteins showed to be under the effect of positive selection, suggesting that amino acid replacements in these proteins resulted in beneficial functional changes. Finally, we have revealed that allelic variation (six and five amino acid exchanges in LILRB1 and LILRB2, respectively) affects the structure and/or stability of both molecules. Nonetheless, LILRB2 has shown higher average stability, with no D1/D2 residue affecting protein structure. Overall, our findings demonstrate that LILRB1 and LILRB2 are as polymorphic as HLA class Ib genes and provide strong evidence supporting the directional selection regime hypothesis.
Vitiligo is the most frequent cause of depigmentation worldwide. Genetic association studies have discovered about 50 loci associated with disease, many with immunological functions. Among them is ...HLA-G, which modulates immunity by interacting with specific inhibitory receptors, mainly LILRB1 and LILRB2. Here we investigated the
and
association with vitiligo risk and evaluated the possible role of interactions between HLA-G and its receptors in this pathogenesis. We tested the association of the polymorphisms of
,
, and
with vitiligo using logistic regression along with adjustment by ancestry. Further, methods based on the multifactor dimensionality reduction (MDR) approach (MDR v.3.0.2, GMDR v.0.9, and MB-MDR) were used to detect potential epistatic interactions between polymorphisms from the three genes. An interaction involving rs9380142 and rs2114511 polymorphisms was identified by all methods used. The polymorphism rs9380142 is an
3'UTR variant (+3187) with a well-established role in mRNA stability. The polymorphism rs2114511 is located in the exonic region of
. Although no association involving this SNP has been reported, ChIP-Seq experiments have identified this position as an EBF1 binding site. These results highlight the role of an epistatic interaction between
and
in vitiligo pathogenesis.
BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an ...oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (−6.6 g/m2 (−11.0 to −2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration number:NCT00925301; Pre-results.
The selection and regulation of individual mRNAs for translation initiation from a competing pool of mRNA are poorly understood processes. The closed loop complex, comprising eIF4E, eIF4G and PABP, ...and its regulation by 4E-BPs are perceived to be key players. Using RIP-seq, we aimed to evaluate the role in gene regulation of the closed loop complex and 4E-BP regulation across the entire yeast transcriptome.
We find that there are distinct populations of mRNAs with coherent properties: one mRNA pool contains many ribosomal protein mRNAs and is enriched specifically with all of the closed loop translation initiation components. This class likely represents mRNAs that rely heavily on the closed loop complex for protein synthesis. Other heavily translated mRNAs are apparently under-represented with most closed loop components except Pab1p. Combined with data showing a close correlation between Pab1p interaction and levels of translation, these data suggest that Pab1p is important for the translation of these mRNAs in a closed loop independent manner. We also identify a translational regulatory mechanism for the 4E-BPs; these appear to self-regulate by inhibiting translation initiation of their own mRNAs.
Overall, we show that mRNA selection for translation initiation is not as uniformly regimented as previously anticipated. Components of the closed loop complex are highly relevant for many mRNAs, but some heavily translated mRNAs interact poorly with this machinery. Therefore, alternative, possibly Pab1p-dependent mechanisms likely exist to load ribosomes effectively onto mRNAs. Finally, these studies identify and characterize a complex self-regulatory circuit for the yeast 4E-BPs.
Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the ...replication-timing programme and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. The role of RIF1 in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing programme and nuclear architecture.
Human leukocyte antigen‐C (HLA‐C) is a classical HLA class I molecule that binds and presents peptides to cytotoxic T lymphocytes in the cell surface. HLA‐C has a dual function because it also ...interacts with Killer‐cell immunoglobulin‐like receptors (KIR) receptors expressed in natural killer and T cells, modulating their activity. The structure and diversity of the HLA‐C regulatory regions, as well as the relationship among variants along the HLA‐C locus, are poorly addressed, and few population‐based studies explored the HLA‐C variability in the entire gene in different population samples. Here we present a molecular and bioinformatics method to evaluate the entire HLA‐C diversity, including regulatory sequences. Then, we applied this method to survey the HLA‐C diversity in two population samples with different demographic histories, one highly admixed from Brazil with major European contribution, and one from Benin with major African contribution. The HLA‐C promoter and 3′UTR were very polymorphic with the presence of few, but highly divergent haplotypes. These segments also present conserved sequences that are shared among different primate species. Nucleotide diversity was higher in other segments rather than exons 2 and 3, particularly around exon 5 and the second half of the 3′UTR region. We detected evidence of balancing selection on the entire HLA‐C locus and positive selection in the HLA‐C leader peptide, for both populations. HLA‐C motifs previously associated with KIR interaction and expression regulation are similar between both populations. Each allele group is associated with specific regulatory sequences, reflecting the high linkage disequilibrium along the entire HLA‐C locus in both populations.
Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is ...unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
Objective
To compare the accuracy of cephalometric landmark identification between artificial intelligence (AI) deep learning convolutional neural networks (CNN) You Only Look Once, Version 3 ...(YOLOv3) algorithm and the manually traced (MT) group.
Setting and sample population
The American Association of Orthodontists Federation (AAOF) Legacy Denver collection was used to obtain 110 cephalometric images for this study.
Materials and Methods
Lateral cephalograms were digitized and traced by a calibrated senior orthodontic resident using Dolphin Imaging. The same images were uploaded to AI software Ceppro DDH Inc The Cartesian system of coordinates with Sella as the reference landmark was used to extract x‐ and y‐coordinates for 16 cephalometric points: Nasion (Na), A point, B point, Menton (Me), Gonion (Go), Upper incisor tip, Lower incisor tip, Upper incisor apex, Lower incisor apex, Anterior Nasal Spine (ANS), Posterior Nasal Spine (PNS), Pogonion (Pg), Pterigomaxillary fissure point (Pt), Basion (Ba), Articulare (Art) and Orbitale (Or). The mean distances were assessed relative to the reference value of 2 mm. Student paired t‐tests at significance level of P < .05 were used to compare the mean differences in each of the x‐ and y‐components. SPSS (IBM‐vs. 27.0) software was used for the data analysis.
Results
There was no statistical difference for 12 out of 16 points when analysing absolute differences between MT and AI groups.
Conclusion
AI may increase efficiency without compromising accuracy with cephalometric tracings in routine clinical practice and in research settings.
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