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Space analog research has increased over the last few years with new analogs appearing every year. Research in this field is very important for future real mission planning, selection and training of astronauts. Analog environments offer specific characteristics that resemble to some extent the environment of a real space mission. These analog environments are especially interesting from the psychological point of view since they allow the investigation of mental and social variables in very similar conditions to those occurring during real space missions. Analog missions also represent an opportunity to test operational work and obtain information on which combination of processes and team dynamics are most optimal for completing specific aspects of the mission. A group of experts from a European Space Agency (ESA) funded topical team reviews the current situation of topic, potentialities, gaps, and recommendations for appropriate research. This review covers the different domains in space analog research including classification, main areas of behavioral health performance research in these environments and operational aspects. We also include at the end, a section with a list or tool of recommendations in the form of a checklist for the scientific community interested in doing research in this field. This checklist can be useful to maintain optimal standards of methodological and scientific quality, in addition to identifying topics and areas of special interest., (© 2024. The Author(s).)

The evaluation of manual Trigger Point Therapy (TrPt) on mandible abduction range of Analog Astronauts (AA) surviving isolation conditions during consecutive missions at the LunAres Habitat was performed. This physiotherapy method was applied to decrease stress-related neuromuscular tension. Abduction measurements were conducted on the two groups of five AA, who endured severe isolation conditions for 14 days in the limited space of the LunAres Research Station Habitat (Piła, Poland) during missions. The test group consisted of abduction measurements of AA who received TrPt and control group of abduction measurements of AA who did not receive TrPt. All measurements were noted in the TemporoMandibular Joint (TMJ) diagnosis aspect of the integrated dental examination card SZOPPDP©. The ischemic compression was performed on an active localized trigger point-resulting in cessation of pain. Maximum abduction measurements were made with an electronic caliper, and the abduction range was compared. The change of abduction range in AA with TrPt was bigger than in AA without TrPt. A larger increase in abduction range was observed in every case in the group receiving TrPt compared to the control group. TrPt effectively decreases the neuromuscular tension, which results in an increased mandibular abduction range of AA. Observations conducted in LunAres Research Station regarding stress-related neuromuscular tension can help identify effective therapeutic methods for circumstances of social isolation.

Analog space missions were created to study the human factor in extraordinary conditions that would occur in future space habitats. Isolation has been shown to cause stress and disrupt individuals' daily routine, which can also affect their oral hygiene and lead to an increased risk of dental caries and gingivitis. The astronauts' specific freeze-dried diet is associated with "lazy" chewing, potential dehydration and vitamin A deficiency, which may adversely affect their saliva. The aim of this study is to investigate the influence of the freeze-dried diet on selected oral hygiene indicators in analog astronauts (AA) enduring strict isolation conditions during six consecutive analog space missions at the LunAres Research Station. During the experiment the oral hygiene and gingival inflammation status measurements were conducted on the group of AAs at the beginning and at the end of each mission. Measurements included four oral hygiene indicators: API, sOHI, PI by Silness and Loe and GBI by Ainamo and Bay. Each AA's individual scores were noted and analyzed. Statistically significant reduction in the amount of plaque and intensity of gingival bleeding was observed over the course of the study, which could indicate positive results of applied oral hygiene procedures despite unfavorable dietary and stressful isolation conditions.

Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Complex mixtures of DNA encoded small molecules may be readily interrogated via high-throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules that interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small molecule moieties of DELs are generally synthesized though a multistep process, and each chemical step is accomplished while it is simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein, protocols for 24 reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multistep synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reactions including BOC deprotection (under pH neutral conditions), carbamylation, and Sonogashira coupling. Last, step-by-step protocols for synthesizing functionalized DELs from trichloronitropyrimidine and trichloropyrimidine scaffolds are detailed.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The ligand H(2)C(PPh(2)BH(3))(2) (-H(2)) reacted with one or a half equivalent of (para-tBu-C(6)H(4)CH(2))(2)Ca.(THF)(4) to form the calcium complexes Ca[HC(PPh(2)BH(3))(2)](2) (-H)(2)Ca and CaC(PPh(2)BH(3))(2) (-Ca), respectively. The crystal structures of their THF adducts (-H)(2)Ca.THF and [-Ca.(THF)](2) follow the same trends as observed for the corresponding iminophosphorano substituted complexes Ca[HC(PPh(2)NR)(2)](2) and [CaC(PPh(2)NR)(2)](2). The P-C bonds shorten upon gradual deprotonation, whereas the P-B and P-N bonds elongate. The geometries of DFT-optimized model systems and complete molecular structures show similar trends. Also the charge distribution within the boranophosphorano complexes is similar to that in the iminophosphorano complexes. The high positive charges on Ca (1.74-1.75) indicate a predominantly ionic ligand-Ca bonding. High negative charges on the central carbon atom (-1.103 in Ca[HC(PH(2)BH(3))(2)](2) and -1.775 in [CaC(PH(2)BH(3))(2)](2)) compare well to those calculated for analogous iminophosphorano complexes (-1.126 Ca[HC(PH(2)NH)(2)](2) and -1.847 [CaC(PH(2)NH)(2)](2), respectively). Thus, in both types of complexes delocalization of electron density over the boranophosphorano or iminophosphorano substituents does not play a major role. Complex [-Ca.(THF)](2) does not react with adamantyl cyanide. Instead the adduct (-Ca)(2).(THF).(adamantyl-C[triple bond, length as m-dash]N) formed (a crystal structure has been determined).

Size does matter: Whereas geminal bimetallic bis(amidophosphorano)methandiide complexes of the heavy alkali metals K and Rb are relatively stable, that of Cs, the largest and most electropositive of the alkali metals, decomposes to form a cyclic product, which cocrystallizes with benzylcesium.

Superbulky sandwich complexes with the cyclopentadienyl ligand (4-nBu-C(6)H(4))(5)Cp (abbreviated here as Cp(BIG)) have been prepared by reaction of Cp(BIG)H with benzylic strontium or barium reagents. Both metallocenes have been structurally characterized by single crystal X-ray diffraction. Even for the larger metallocene (Cp(BIG))(2)Ba a highly symmetric sandwich complex with parallel Cp rings was isolated (Cp(center)-Ba = 2.667(1) A). Both structures show evidence for a C-HC(pi) network between the Cp ligands. These attractive forces induce an inward out-of-plane bending of the aryl substituents (Sr 3.4(2) degrees; Ba 5.3(2) degrees). A linear correlation between this bending angle and metal size has been found.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Attempted 2-fold deprotonation of the bis(iminophosphorano)methane ligand, H(2)C(Ph(2)P=NSiMe(3))(2) (4-H(2)), with a calcium amide led only to mono-deprotonation. The crystal structure of (4-H)(2)Ca shows two tridentate ligands with short Ca-N and a rather long Ca-C bond. Reaction of 4-H(2) with a dibenzylcalcium complex gave the desired 2-fold deprotonation and formation of 4-Ca, which crystallized as a dimeric complex. Analysis of the calculated atomic and group charges in 4-H(2), (4-H)(2)Ca, and [4-Ca](2) showed that the negative charge at the imine nitrogens only slightly increases upon successive deprotonation of 4-H(2). The electron density at the central carbon, however, increases considerably: the charge on the carbene carbon in [4-Ca](2) is ca. -1.8. The negative charge in 4(2)(-) is therefore mainly located on the carbon. Reaction of [4-Ca](2) with benzophenone in benzene gave the remarkably stable adduct [4-Ca](2) x O=CPh(2), which was characterized by X-ray diffraction. Reaction of [4-Ca](2) with adamantylcyanide gave exclusive formation of the adduct [4-Ca](2) x (N identical withCR)(2), which did not react further, even at higher temperatures. Addition of cyclohexyl isocyanate to a benzene solution of [4-Ca](2) gave immediate [2 + 2]-cycloaddition and formation of a dianionic tetradentate ligand that binds to Ca(2+) through two nitrogens, the central carbon, and an oxygen. This product crystallized as a dimer with bridging oxygen atoms.

Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.