Trajectories of Adolescents Treated with Gonadotropin-Releasing Hormone Analogues for Gender Dysphoria

Gonadotropin-releasing hormone analogues (GnRHa) are recommended as initial treatment for adolescents diagnosed with gender dysphoria, providing time to follow gender identity development and consider further treatment wishes without distress caused by unwant

How Feeling Understood Predicts Trust and Willingness to Forgive in the Midst of Violent Intergroup Conflict: Longitudinal Evidence From Ukraine

This is the final version. Available on open access from SAGE Publications via the DOI in this record.How can intergroup trust and forgiveness be fostered in the face of violent, large-scale intergroup conflict? We addressed this challenge by testing the role of intergroup felt understanding—the extent to which outgroup members are perceived to understand ingroup perspectives—in predicting Ukrainian nationals’ inclinations to trust and forgive Russians for the conflict that has affected Ukraine since 2014. We did so using representative longitudinal data ( N = 743; three time points) collected 6 months before Russia’s full-scale invasion. Pre-registered analysis of dynamic mediation models confirmed that increases over time in felt understanding predicted increases over time in perceived positive regard, which in turn predicted increased outgroup trust and forgiveness over time. A mini-multiverse analysis indicated that this pattern was also largely robust to varying time point specifications. The findings provide further evidence that the feeling of being understood may be a key psychological factor that enables reconciliation

N-{(2S)-3-Hy­droxy-4-[(5-methyl-1,3,4-thia­diazol-2-yl)sulfan­yl]-1-phenyl-2-but­yl}-4-methyl­benzene­sulfonamide

The thia­diazoyl and sulfonyl-benzene rings in the title compound, C20H23N3O3S3, are aligned to the same side of the mol­ecule, forming a twisted ‘U’ shape [dihedral angle = 77.6 (5)°]. The benzyl-benzene ring is orientated in the opposite direction from the mol­ecule but projects approximately along the same axis as the other rings [dihedral angle between benzene rings = 28.2 (5)°] so that, overall, the mol­ecule has a flattened shape. The hy­droxy and amine groups are almost syn which enables the formation of inter­molecular hy­droxy-OH⋯N(thia­diazo­yl) and amine-H⋯O(sulfon­yl) hydrogen bonds leading to a supra­molecular chain aligned along the a axis

svmPRAT: SVM-based Protein Residue Annotation Toolkit

<p>Abstract</p> <p>Background</p> <p>Over the last decade several prediction methods have been developed for determining the structural and functional properties of individual protein residues using sequence and sequence-derived information. Most of these methods are based on support vector machines as they provide accurate and generalizable prediction models.</p> <p>Results</p> <p>We present a general purpose protein residue annotation toolkit (<it>svm</it><monospace>PRAT</monospace>) to allow biologists to formulate residue-wise prediction problems. <it>svm</it><monospace>PRAT</monospace> formulates the annotation problem as a classification or regression problem using support vector machines. One of the key features of <it>svm</it><monospace>PRAT</monospace> is its ease of use in incorporating any user-provided information in the form of feature matrices. For every residue <it>svm</it><monospace>PRAT</monospace> captures local information around the reside to create fixed length feature vectors. <it>svm</it><monospace>PRAT</monospace> implements accurate and fast kernel functions, and also introduces a flexible window-based encoding scheme that accurately captures signals and pattern for training effective predictive models.</p> <p>Conclusions</p> <p>In this work we evaluate <it>svm</it><monospace>PRAT</monospace> on several classification and regression problems including disorder prediction, residue-wise contact order estimation, DNA-binding site prediction, and local structure alphabet prediction. <it>svm</it><monospace>PRAT</monospace> has also been used for the development of state-of-the-art transmembrane helix prediction method called TOPTMH, and secondary structure prediction method called YASSPP. This toolkit developed provides practitioners an efficient and easy-to-use tool for a wide variety of annotation problems.</p> <p><it>Availability</it>: <url>http://www.cs.gmu.edu/~mlbio/svmprat</url></p

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer)

Catalytic Water Co-Existing with a Product Peptide in the Active Site of HIV-1 Protease Revealed by X-Ray Structure Analysis

BACKGROUND: It is known that HIV-1 protease is an important target for design of antiviral compounds in the treatment of Acquired Immuno Deficiency Syndrome (AIDS). In this context, understanding the catalytic mechanism of the enzyme is of crucial importance as transition state structure directs inhibitor design. Most mechanistic proposals invoke nucleophilic attack on the scissile peptide bond by a water molecule. But such a water molecule coexisting with any ligand in the active site has not been found so far in the crystal structures. PRINCIPAL FINDINGS: We report here the first observation of the coexistence in the active site, of a water molecule WAT1, along with the carboxyl terminal product (Q product) peptide. The product peptide has been generated in situ through cleavage of the full-length substrate. The N-terminal product (P product) has diffused out and is replaced by a set of water molecules while the Q product is still held in the active site through hydrogen bonds. The position of WAT1, which hydrogen bonds to both the catalytic aspartates, is different from when there is no substrate bound in the active site. We propose WAT1 to be the position from where catalytic water attacks the scissile peptide bond. Comparison of structures of HIV-1 protease complexed with the same oligopeptide substrate, but at pH 2.0 and at pH 7.0 shows interesting changes in the conformation and hydrogen bonding interactions from the catalytic aspartates. CONCLUSIONS/SIGNIFICANCE: The structure is suggestive of the repositioning, during substrate binding, of the catalytic water for activation and subsequent nucleophilic attack. The structure could be a snap shot of the enzyme active site primed for the next round of catalysis. This structure further suggests that to achieve the goal of designing inhibitors mimicking the transition-state, the hydrogen-bonding pattern between WAT1 and the enzyme should be replicated

Developing optimal input design strategies in cancer systems biology with applications to microfluidic device engineering

<p>Abstract</p> <p>Background</p> <p>Mechanistic models are becoming more and more popular in Systems Biology; identification and control of models underlying biochemical pathways of interest in oncology is a primary goal in this field. Unfortunately the scarce availability of data still limits our understanding of the intrinsic characteristics of complex pathologies like cancer: acquiring information for a system understanding of complex reaction networks is time consuming and expensive. Stimulus response experiments (SRE) have been used to gain a deeper insight into the details of biochemical mechanisms underlying cell life and functioning. Optimisation of the input time-profile, however, still remains a major area of research due to the complexity of the problem and its relevance for the task of information retrieval in systems biology-related experiments.</p> <p>Results</p> <p>We have addressed the problem of quantifying the information associated to an experiment using the Fisher Information Matrix and we have proposed an optimal experimental design strategy based on evolutionary algorithm to cope with the problem of information gathering in Systems Biology. On the basis of the theoretical results obtained in the field of control systems theory, we have studied the dynamical properties of the signals to be used in cell stimulation. The results of this study have been used to develop a microfluidic device for the automation of the process of cell stimulation for system identification.</p> <p>Conclusion</p> <p>We have applied the proposed approach to the Epidermal Growth Factor Receptor pathway and we observed that it minimises the amount of parametric uncertainty associated to the identified model. A statistical framework based on Monte-Carlo estimations of the uncertainty ellipsoid confirmed the superiority of optimally designed experiments over canonical inputs. The proposed approach can be easily extended to multiobjective formulations that can also take advantage of identifiability analysis. Moreover, the availability of fully automated microfluidic platforms explicitly developed for the task of biochemical model identification will hopefully reduce the effects of the 'data rich-data poor' paradox in Systems Biology.</p

Correlated Mutations: A Hallmark of Phenotypic Amino Acid Substitutions

Point mutations resulting in the substitution of a single amino acid can cause severe functional consequences, but can also be completely harmless. Understanding what determines the phenotypical impact is important both for planning targeted mutation experiments in the laboratory and for analyzing naturally occurring mutations found in patients. Common wisdom suggests using the extent of evolutionary conservation of a residue or a sequence motif as an indicator of its functional importance and thus vulnerability in case of mutation. In this work, we put forward the hypothesis that in addition to conservation, co-evolution of residues in a protein influences the likelihood of a residue to be functionally important and thus associated with disease. While the basic idea of a relation between co-evolution and functional sites has been explored before, we have conducted the first systematic and comprehensive analysis of point mutations causing disease in humans with respect to correlated mutations. We included 14,211 distinct positions with known disease-causing point mutations in 1,153 human proteins in our analysis. Our data show that (1) correlated positions are significantly more likely to be disease-associated than expected by chance, and that (2) this signal cannot be explained by conservation patterns of individual sequence positions. Although correlated residues have primarily been used to predict contact sites, our data are in agreement with previous observations that (3) many such correlations do not relate to physical contacts between amino acid residues. Access to our analysis results are provided at http://webclu.bio.wzw.tum.de/~pagel/supplements/correlated-positions/