Amine bases are shown to induce reductive elimination of dihydrogen from terphenyltin trihydride. ii) hydrides have been an iconic class of compounds in molecular main group chemistry. Among other approaches they have been accessed from the hydrogenation of distannynes. We herein report their accessibility from the other direction by dehydrogenation of organotin trihydride. On reacting pyridine and amine bases with the bulky substituted organotin trihydride Ar*SnH3 –, trip = 2,4,6-triisopropylphenyl) hydrogen evolution was observed. In case of catalytic amounts of base the dehydro-coupling product diorganodistannane Ar*H2SnSnH2Ar* was obtained quantitatively whilst for excessive amounts (>4 eq.) the monomeric base adduct to known Ar*SnH was obtained almost exclusively. The base adducts were found to be remarkably thermally robust. They readily react with polar fulvenic C PBM data was replaced with SVG by xgml2pxml:<glyph-data id="z.dbd" format="PBM" resolution="300" x-size="34" y-size="34" xml:space="preserve"> 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000	</glyph-data><svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="16.000000pt" height="16.000000pt" viewBox="0 0 16.000000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata>Created by potrace 1.16, written by Peter Selinger 2001-2019</metadata><g transform="translate scale" fill="currentColor" stroke="none"><path d="M0 1440 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z M0 960 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z"/></g></svg>C-bonds in hydro-stannylenylation reactions. The resulting half-sandwich complex Ar*SnCp* was structurally characterized. Moreover, on application of less nucleophilic amine bases, the uncoordinated, in solution dimeric [Ar*SnH]2 is formed. NMR spectroscopic studies on the kinetics of the DMAP-catalysed reductive elimination of dihydrogen were performed. The activation energy was approximated to be 13.7 kcal mol–1. Solvent dependencies and a kinetic isotope effect KIE of kH/kD = 1.65 in benzene and 2.04 in THF were found and along with DFT calculations support a polar mechanism for this dehydrogenation.Since their first description over a decade ago, organotin( Located between these two extremes tin forms stable di- and tetravalent salts and thus reveals a more sophisticated relationship between di- and tetravalency.In the periodic table, tin is located at an intriguing borderline position in terms of the stability of its di- and tetravalent derivatives. As the fifth period representative of the carbon group 14 it thermodynamically prefers formation of tetravalent compounds in the oxidation state +4 yet it benefits from the markedly increased effect of the inert pair for heavier elements. Whilst divalent compounds of its lighter congener Ge are easily oxidized toward Ge halides or by various reduction approaches of the diorganotin dihalides.3 A highly underestimated class of potential precursors for low-valent tin chemistry are tetravalent hydrides of the general composition RnSnHn4– with n ≤ 2. Owing to the weak tin–hydrogen bond these compounds represent potential precursors for the generation of divalent Sn(ii) species by removal of dihydrogen. Observations of a catalytic approach towards evolution of dihydrogen from tin dihydrides date back to seminal contributions of Kuivila et al. and Neumann et al. in the early 1960s who reported on formamide and base catalysed dehydrogenation from diphenyltin dihydride (and other diorganotin dihydrides) and isolation of yellow solids that were characterized as polymeric or oligomeric diorganotin. Many years later the concept was revisited and also transition metal catalysts have been applied to perform selective dehydrocoupling reactions with tin dihydrides to obtain tetraorganodistannanes or organotin polymers  has always been a challenging task due to their generally high sensitivity toward ambient oxidative atmosphere.polymers .17–23 24 Depending on the exact stoichiometric ratio of the carbene vs. tin hydride either dehydrocoupling was achieved or the adducts of carbenes to stannylenes and organotin(ii) hydrides were obtained. Organotin(ii) hydrides are an intriguing class of compounds that have first been reported by seminal works of Power et al. Computational predictions for dimers of the parent SnH2 indicated various isomers with low isomerisation barriers. Some of the structural motifs predicted computationally have been experimentally observed  is the substitution pattern of the terphenyl moiety applied whereas different isomers may be observed in solid-state and in solution  hydrides D monomeric in solid state were described by Jones et al. who also reported their catalytic applicability in hydroboration reactions. Examples for donor-stabilized β-diketiminate tin(ii) hydrides E and pincer-type complexes F and their reactivity in hydro-elementation reactions were reported. Parent [SnH2] was shown to be successfully stabilized in a donor–acceptor bisadduct complex  we are not aware of any systematic study on bulky substituted dihydrides. Moreover, to the best of our knowledge, reactions of organotin trihydrides and amine bases have not been investigated previously in the literature. We now consider organotin trihydrides with substituents of sufficient steric bulk to provide kinetic stabilization to yield the respective organotin(ii) hydride upon hydrogen release catalysed by an amine base. The conditions under which these hydrides are synthetically accessed are so far limited to metathesis of ArSn(ii) halides, hydroboration of ArSn(ii) amides, Sn–C hydrogenolysis of bulky stannylenes, and importantly, hydrogenation of distannynes ArSnSnAr (Ar = various bulky terphenyl moieties). The reverse reaction to form donor stabilized distannynes via dehydrogenation of unstable organotin(ii) hydride intermediates is also known.47We realized that the dehydrogenation of organotin hydrides induced by simple amine bases has only been applied for the generation of higher aggregate stannanes but apart from phenii) hydrides that does not rely on low-oxidation state precursor materials to represent a valuable addition for the synthesis of these species. Furthermore reductive eliminations in general are critical steps in many transition metal catalysed transformations but are less common for main group elements.48 The phenomenon of a readily occurring reductive elimination to produce low-valent species in the main groups represents a reaction of general interest to the chemical community in the development and understanding of main group catalysed reactions.48From a general synthetic perspective we consider a synthetic protocol toward organotin2Sn-bridged vs. stannylstannylene SnSnH2). This is in accordance with the computationally obtained small energetic differences between the various potential isomers and low-activation energy barriers for their interconversion. Even with large excess of hydrogen no further hydrogen uptake towards distannane ArH2Sn–SnH2Ar or even ArSnH3 was observed, even though the reaction was computed to be thermodynamically favourable. This contrasts the observations for the digermyne reaction under hydrogen atmosphere which yielded mixtures of ArHGeGeHAr, ArH2GeGeH2Ar and ArGeH3.50 This deviating reaction behaviour was further discussed in an extensive computational study that provided further insight into the mechanism of the hydrogen uptake reaction and rearrangement/isomerization processes in the hydrogenated species.49 For the Ar′-system C6H3–), the free hydrogenation enthalpy for the hydrogen uptake from monomeric Ar′SnH to Ar′SnH3 was computed to be slightly exergonic . Nevertheless, the energy barrier  for this reaction and accordingly even more for the reverse dehydrogenation reaction was found to be too high to proceed.49In the course of their studies toward the hydrogenation of group 14 dimetallynes Power 3 (1)  to form monomeric Ar*SnH J and dihydrogen is found to be endothermic  but slightly exergonic . When the experimentally observed dimerization of the monomeric Ar*SnH J is taken into account, the overall reaction becomes thermodynamically favourable . These preliminary energetic approximations further supported our interest to study possible dehydrogenations of Ar*SnH3.According to our calculated enthalpies in the gas phase (BP86/def2-TZVP) the dehydrogenation of Ar*SnH3 (1) with the bulky Ar* terphenyl-moiety since it has impressively been shown to stabilize the seminal [Ar*SnH]2 (H) accessed by different approaches and thus ensures the stability of potential products. Ar*SnH3 (1) is conveniently obtained by metathesis of the organotin trichloride Ar*SnCl3 (2) and LiAlH4 in ethereal solutions. However, attempts toward synthesis of 2 from Ar*Li and SnCl4 were found to yield mixtures including several hardly separable side-products (Ar*Cl and Ar*H). Oxidative approaches including the chlorination of the conveniently accessible and readily crystallizing Ar*SnCl 3 with some chlorination agents such as PCl3 or CCl4 were reported in the literature, yet reveal unsatisfactory yields and need further purification procedures. We found mercury(ii) chloride to be a perfectly suitable oxidizing agent for the chlorination of 3. Addition of stoichiometric amounts of HgCl2 to cooled solutions of Ar*SnCl 3 in toluene result in immediate decolourisation of the solution and most likely formation of transient Ar*SnCl2HgCl. On warming to room temperature mercury precipitates and after isolation of the supernatant solution and extraction with hexane Ar*SnCl32 can be isolated in quantitative yield in elemental analysis grade purity without further purification.For our studies we chose Ar*SnH1 with various equivalents of pyridine bases. Initial experiments involving the application of one equivalent of 4-dimethylaminopyridine (DMAP) in benzene at room temperature revealed a slow change of the solutions from colorless to yellow. The formation of a gas is indicated by occasional observation of bubbles. For solutions of [Ar*SnH]2H a blue color was described by Power.1H- as well as 119Sn-NMR spectroscopic surveillance of the reaction progress revealed ongoing consumption of the starting material Ar*SnH31 along with formation of a mixture of compounds, among which dihydrogen can be clearly identified by its characteristic signal at δ = 4.47 ppm in the 1H NMR spectra. When kept at room temperature the reaction was finished within ten days. 1H-coupled 119Sn NMR spectroscopy of the intense yellow solution revealed two sets of signals, yet not the signals expected for [Ar*SnH]2H. A doublet was found at δ = 225 ppm with a rather small coupling constant of JSnH = 116 Hz and a spectrum of higher order 2Sn–Sn(H)2Ar* (4). The dimensions of the observed coupling constants agree well with 1JSnH and 2JSnH coupling constants known in the literature.3We studied the reactions of r see ESI includin5 which represents the DMAP base-adduct to the Lewis-acidic tin(ii) moiety of the monomer of H, Ar*SnH J. The 1JSnH = 116 Hz coupling constant is strongly reduced compared to the coupling observed for the donor-free H [Ar*SnH]2 of 594 Hz. In solution H most likely exists as the stannylstannylene-type isomer Ar*SnSnH2Ar* BH  hydride complexes with terminal Sn–H bond such as found in the carbene adduct Ar*SnH(NHC) (223 Hz)24 and diketiminate/pincer complexes E and F (64/112 Hz).The second signal at lower field can be assigned to Ar*SnH(DMAP) 31 under formation of the base-adduct 5 to the monomeric hydrido stannylene Ar*SnH J. Diorganodistannane 4 is then most likely formed by insertion of intermediately formed J into the Sn–H bond of Ar*SnH31. From the observed generation of distannane 4 we conclude that there has to be an equilibrium between Ar*SnH(DMAP) 5 and uncoordinated Ar*SnH J that provides sufficient amounts of J for subsequent reactions  of DMAP base. As expected, distannane 4 is formed quantitatively along with traces of Ar*SnH(DMAP) 5. At room temperature the reaction proceeded slowly (up to three weeks), but on warming to 65 °C Ar*SnH31 was consumed within three days and no significant side products were observed. This is interesting since especially organotin trihydrides are usually thermally sensitive and often decompose under formation of elemental tin. Mixtures of distannane 4 and DMAP remained stable and no further elimination of dihydrogen was observed. Along with ligand-related resonances, 1H NMR spectra of 4 revealed the Sn–H protons at δ = –3.93 ppm accompanied by the satellites reflecting the complex mixture of 117/119Sn isotopomers  5 and successful suppression of the subsequent reaction that yields distannane 4. Whilst three equivalents of base allowed formation of 4 mol% of 4 as a side product only about 0.2 mol% were formed on application of ten equivalents of DMAP  5 and excessive DMAP revealed a broad singlet at δ = 11.6 ppm accompanied by tin satellites with an integration ratio corresponding to the natural abundance of NMR active tin isotopes strongly indicating the monomeric nature of the species. The signal is assigned to the Sn–H proton and is low-field shifted compared to the NMR spectroscopic features of [Ar*SnH]2H. The shift compares well with Roesky's three coordinate Sn–H complexes E.41 The DMAP adduct to a bulky amido tin hydride was reported by Jones.34The 5 and DMAP in solution revealed remarkable thermal stability. Even upon prolonged heating to 85 °C no decomposition was observed. For [Ar*SnH]2H and related terphenyl tin(ii) hydride [Ar′SnH]2 decomposition with dehydrogenation and ligand stripping under formation of metal-rich clusters is known in refluxing toluene. The carbene-adduct of the much less bulky substituted tripSnH(NHC) K  generated in situ is thermally sensitive and already decomposes at temperatures above –20 °C.24 Upon heating, the Sn–H resonance of 5 gradually broadened and shifted toward lower field by 0.2 ppm at 85 °C. The Sn–H coupling constant decreased by approx. 5 Hz each 10 K. This was accompanied by a sharpening of DMAP related signals at elevated temperatures along with subtle shifts of the DMAP related signals. With high excess of DMAP the related signals were found to be much sharper. These findings indicate a dynamic exchange of coordinated and free DMAP. Unfortunately, all attempts to crystallize 5 from these mixtures remained unsuccessful.The mixtures of 5 and DMAP were removed in vacuo, yellow solutions were obtained by extraction with pentane along with a residual white solid that corresponds to approx. 80–90% of the excessive DMAP. Storage of these extracts at –40 °C led to further crystallization of colorless DMAP and yellow solutions. When these solutions were again separated from the crystallized solid and subsequently warmed to room temperature they immediately turned pale green. On storing these solutions at –40 °C they turned back to yellow and yellow crystals were obtained within four days. X-ray diffraction did not reveal the expected moiety of Ar*SnH(DMAP) 5 but the DMAP adduct to the stannylstannylene-type isomer BH Ar*Sn(DMAP)SnH2Ar* 6 (When the solvents of the reaction mixtures of nH2Ar* 6 .6 include a Sn–Sn bond of 2.8792(3) Å which is slightly shorter as found for the bulkier substituted uncoordinated stannylstannylenes (2.916/2.924 Å). The Sn–DMAP vector is almost perpendicular to the Cipso–Sn1–Sn2 plane in accord with an electron donating interaction into the empty p-orbital at the stannylene Sn atom, which becomes a stereochemically active centre. However, NMR spectroscopy indicates a dynamic behaviour in solution SnH2Ar* 6 at room temperature revealed broad ligand related sets of signals and Sn–H signals likely corresponding to Ar*SnH(DMAP) 5. Broad DMAP related signal sets allow assumption of a dynamic equilibrium leading to compound mixtures. The same broad 1H NMR spectrum was obtained upon addition of 0.5 equivalents of DMAP to solutions of H obtained from an alternative approach (vide infra). The assumption of an equilibrium is further supported by the observation of four resonances in the 119Sn NMR spectrum at δ = 698 , 398 (6-SnN), 225 (5) and –248 (6-SnH2) ppm. These represent all compounds of the equilibrium proposed in 6 to –40 °C well resolved NMR spectra could be obtained with sharp signal sets for all species. A set of signals in the spectra can be assigned to the adduct of a stannylstannylene which indicates the presence of 6 in solution. The tin hydride resonances appeared as two separate singlets at δ = 5.60 and 5.51 ppm in accord with the chiral environment at the neighbouring DMAP coordinated stannylene Sn atom. The inequivalency of the hydride signals is also reflected in the coupling pattern of the respective 119Sn resonance (6-SnH2) as a doublet of doublet with coupling constants of 1JSn–H = 1230 and 1040 Hz. The chemical shift of both tin resonances in 6 are in accord with literature values for base-adducts to stannylenes and tin dihydrides. IR spectra revealed stretching and bending frequencies of the Sn–H bonds to be at 1763 cm–1 and 600 cm–1. A donor-adduct to an analogous germylgermylene was previously reported by Power.6131 with a vast excess of pyridine  the reaction proceeded much slower than with DMAP. After one day at room temperature only 30% of Ar*SnH31 was consumed. However NMR spectroscopic examinations indicate formation of the pyridine adduct Ar*SnH(py) 7 analogous to Ar*SnH(DMAP) 5. The characteristic Sn–H resonances were found at δ = 386 ppm (119Sn) and 12.11 ppm . In neat, carefully dried pyridine Ar*SnH31 is less soluble leading to cloudy suspensions and no obvious reaction was observed at room temperature. On heating of the mixtures above 80 °C 1 dissolved and a vivid evolution of gas was observed along with a colour change of the solution to yellow. Although pyridine is used as the solvent and therefore in vast excess, formation of approx. 2–4 mol% of distannane 4 was observed from these mixtures. Compared with the findings for excessive application of DMAP, this indicates that the desired suppression of the distannane formation by forcing the putative equilibrium between Ar*SnH(py) 7 and free Ar*SnH J with high excess of pyridine towards the expectably less reactive adduct species 7 is overcompensated by the expectably less stable stannylene adduct of pyridine vs. DMAP. DFT calculations (BP86/def2TZVP) were run to approximate the free bond dissociation energies (BDE) for cleavage of base adducts to monomeric Ar*SnH J.62 The computed BDE reflect the weaker adducts formed with pyridine Ar*SnH(py) 7  compared to Ar*SnH(DMAP) . The lower dissociation energy is also reflected in the observation of a subtle but obvious color change from yellow toward a pale green when the pyridine solutions were heated to approx. 90 °C in an NMR tube, putatively indicating the presence of a small amount of the blue compound [Ar*SnH]2H. This was not observed for solutions of Ar*SnH(DMAP) 5 with excessive DMAP. The NMR spectra of the reaction mixture in pyridine reproducibly revealed the formation of a further, yet not assigned side product with a 119Sn resonance close to the Sn–H signal (δ = 383 ppm). This side product is most likely an isomer or solvate complex in equilibrium with Ar*SnH(py) 7 since it was completely consumed in trapping experiments with tetramethyl fulvene (vide infra) to yield the identical product. The obviously higher activation energy for the dehydrogenation using pyridine may be rationalized by either the lower nucleophilicity or lower basicity of pyridine (vide infra).When parent pyridine was applied in THF solutions of Ar*SnHii) hydrides it was highly desirable to find conditions under which the uncoordinated [Ar*SnH]2H could be generated. DFT computations indicated that an even lower BDE could be expected for adducts of trialkylamine bases such as NMe3 . The lower BDE may result from both electronic as well as steric effects from interaction with the bulky terphenyl moiety Ar*. Therefore we tested the applicability of various alkyl amines. When a twenty fold excesses the sterically demanding Hünigs base i-Pr2NEt, which is generally considered a strong non-nucleophilic base, was tested a slow color change to a deep blue was observed. Ar*SnH31 was consumed quantitatively after 36 h and 1H NMR spectroscopy revealed the formation of a mixture of three compounds including the signal sets of stannylstannylene type isomer [Ar*SnH]2BH (approx. 50 mol%), distannane 4 (35 mol%) and an unknown compound (15 mol%). This unknown compound featured a Sn–H resonance at δ = 9.68 ppm and revealed broad tin satellites with JSn–H = 91.3 Hz. At first we expected the resonance to correspond to a base adduct Ar*SnH(Ni–Pr2Et). However, the integration ratio of the signals 119Sn satellites with respect to the NMR inactive isotopomer resonance reflected twice the natural abundance of NMR active tin nuclei. This strongly indicates the presence of a hydride species coupling with two magnetically equivalent tin atoms, as it is realized in the μ-H-bridged isomer Ar*Sn(μ-H)2SnAr* AH. To the best of our knowledge, solutions of [Ar*SnH]2H have so far only been reported to reveal the signal sets for the stannylstannylene isomer BH. Observation of the μ-H-bridged isomer Ar*Sn(μ-H)2SnAr* AH may be attributed to the different polarity of the solvent mixtures including the amine, or a further isomerization pathway that is opened by the amine base present allowing an equilibrium in solution. Along with the small coupling constant the assignment of the resonance at δ = 9.68 ppm to the hydrogen bridged isomer to Ar*Sn(μ-H)2SnAr* AH is in accord with Power's observations in extended studies on the structural peculiarities of various terphenyl tin(ii) hydrides. The assumption is further supported by chemical derivatisation experiments (vide infra).In order to further expand the synthetic value of this dehydrogenative approach as a more general route toward organotin or Et2NMe were tested. After a few seconds the mixtures revealed a pale yellow colour (for Et2NMe) that quickly turned deep blue after a few minutes. The reactions were finished within a few hours. NMR spectroscopy revealed these solutions to almost exclusively contain BH and AH (approx. 95%) in a molar ratio of approximately 4 : 1. The molar ratio of BH to AH was found to be independent of the amount of amine base present in solution. We assign the initially observed yellow colour to Ar*SnH(NR3) adducts which are present in dilute solutions of newly generated Ar*SnH J and excessive amine. Due to the weak donor-interaction of the amine we expect that upon increasing concentrations of Ar*SnH(NR3) in the course of the dehydrogenation, deep blue dimeric H is formed. Distannane 4 was formed to a negligible degree . At room temperature, the solutions remained stable and no decomposition was observed for days. Nevertheless, when volatiles including the amines were removed in vacuo at room temperature, examinations of the pale green to yellowish residue revealed further side-products (mainly Ar*SnH which may stem from ligand stripping).58 This is surprising since H was found to be isolable and stable in the solid state.25 This limits the preparative value of the approach. From a practical perspective, Et2NMe was used preferably since it is much easier removed in vacuo.The observed formation of larger amounts of distannane 5, Ar*SnH(py) 7 and the isomer mixtures of [Ar*SnH]2AH/BH obtained by this dehydrogenation approach, trapping experiments of the Sn(ii)–H moiety have been conducted using 1,2,3,4-tetramethyl fulvene. On addition of stoichiometric amounts of fulvene to monomeric adducts Ar*SnH(DMAP) 5 and Ar*SnH(py) 7 an immediate addition of the Sn(ii)–H bond to the polar fulvenic CC double bond was observed quantitatively yielding the bright yellow half-sandwich complex Ar*SnCp* 8 in a hydrostannylenylation reaction  or DMAP (>1 eq.) are added to the green mixtures, bright yellow Ar*SnCp* 8 forms instantly. We suggest that the donor addition forces monomerization and therefore conversion into a more reactive species. After removal of all volatiles Ar*SnCp* 8 could be obtained as a bright yellow solid and crystals suitable for X-ray diffraction could be obtained from concentrated solutions in pentane at –40 °C (In order to test the reactivity and preparative applicability of the crude solutions of Ar*SnH(DMAP) reaction . Additiot –40 °C .8 reveals the half-sandwich complex of tin(ii) and its strong structural relation to the known silicon homologue Ar*SiCp*.63 In solid state, the Cp* moiety reveals closer contacts to three carbon atoms in a η3-fashion. The tin atom deviates from the aromatic plane of the central phenyl group by almost 18° which may be in line with an unusually pronounced low-field shift of the ipso-C atom resonance in the 13C NMR spectrum at δ = 195.7 ppm. This arrangement maybe due to a pronounced polarization of the Sn–C single bond with large ionic character. In case of core Cp*–carbon atoms with strong Sn–C interactions, the methyl groups attached lay below the Cp-ring plane whilst the other methyl moieties are slightly twisted into the other direction. Compared to decacoordinated Cp*2Sn, the inhomogeneity in Sn–C contacts is increased. The shortest Sn–C5 contact in Ar*SnCp* 8 is almost 0.2 Å shorter than in Cp*2Sn, whilst the longest distances are almost 0.1 Å longer.64 The C5 C–C bond lengths are as described for Ar*SiCp* and reveal one short C–C contact. Power reported on Cp derivatives of ArECp  from reactions of the respective dimetallynes with CpH.65 The related η3-coordinated allyl complex Ar*Sn–allyl was reported only recently.66 In solution the Cp* moiety reveals only one resonance in 1H NMR spectroscopy, indicating dynamic exchange on the NMR time scale. 119Sn NMR resonance is found at δ = –25 ppm which is well in accord with the literature for a half-sandwich complex.65Structural characterization of Ar*SnCp* 31 several experiments were conducted. As a model system for studies on mechanistic aspects of the reaction we choose the reaction of Ar*SnH31 with six equivalents of the weighable DMAP in d6-benzene. The experiments were performed with Ar*SnH31 obtained from various crops and different synthetic routes in order to minimize possible systematic errors derived from undetected impurities that are potentially involved in the process. Ar*SnH31 cannot be purified by distillation, therefore halide contamination with hardly detectable amounts of potential catalytically active impurities cannot be rigorously excluded. Therefore to test earlier suggestions of a halide promoted process (vide infra) traces (up to 5%) of organotin trichlorides such as (trip)SnCl3 were added to the reaction mixtures. Hydride/chloride exchange reactions between organotin chlorides and hydrides to form mixed hydrochloro stannanes are known in the literature.67 However, apart from organotin halide derived side products (such as trip–H) and a tin metal mirror, we did not observe any significant acceleration of the reaction compared to the model system (vide infra).In order to further study the mechanism underlying the observed amine-induced reductive elimination of dihydrogen from Ar*SnHl system . Though 31 several experiments were conducted. To suppress the side reaction forming distannane 4, pseudo-first order conditions with excess of DMAP were chosen. From these experiments by observation of the time-dependent consumption of Ar*SnH31via1H NMR spectroscopy we conclude that the reaction proceeded via first order in the DMAP concentration, since the determined rate constants k′ were found to be directly proportional to the concentration of DMAP. Furthermore from an Arrhenius analysis by temperature-dependent measurements of the reaction rates the activation energy of the dehydrogenation in d6-benzene was determined to be 13.7 ± 1.0 kcal mol–1.68 For this model reaction at 313 K a kinetic isotope effect k′H/k′D (KIE) was found to be around KIE ≈ 1.65 in d6-benzene and KIE ≈ 2.04 in d8-THF.68 The maximum KIE for Sn–H/D cleavage was approximated from the stretching frequencies of Ar*SnH3 and Ar*SnD3 to be KIEmax ≈ 3.4.69 In the more polar solvent THF the reaction is almost twice as fast with k′thf/k′benzene ≈ 2.0 ± 0.1 (In order to gain insight into the mechanism that enables the observed amine-induced reductive elimination of dihydrogen from tin trihydride Ar*SnH.0 ± 0.1 . The prevs. basicity) of the amine bases that enables the reaction to proceed, a series of amine bases were tested on their reactivity with Ar*SnH31  was found to be only active at elevated temperatures. In a clean reaction  only formation of distannane 4 was observed. When an exceptionally strong and almost non-nucleophilic amine base such as proton sponge  was used, a very slow reaction was only observed under harsh conditions forming exclusively distannane 4. This reaction behaviour may also result from trace impurities such as other amine bases contained in the proton sponge sample with proton sponge itself being completely incapable to act as dehydrogenation catalyst. As already described, for tertiary alkyl amines the uncoordinated dimeric organotin(ii) hydride H was obtained, with the sterically demanding i-Pr2NEt yielding significant amounts of product 4. When the heavier homologue of TMEDA 1,2-bis(dimethylphosphino)ethane (dmpe) was used, no dehydrogenation reaction was observed even at elevated temperatures. However, when TMEDA was added to the mixture of Ar*SnH31/dmpe, dihydrogen evolved followed by putative formation of the phosphine adduct Ar*SnH(dmpe). Dynamic coordination behaviour in solution is indicated by a broad 31P NMR resonance at δ = –48 ppm and a significant change in the 1H NMR spectrum revealing the Sn–H resonance at δ = 7.80 ppm with coupling constants of JSn–H = 150 Hz. Since in the presence of dmpe dimerization of Ar*SnH to form H is energetically disfavoured compared to formation of the adduct Ar*SnH(dmpe), the phosphine donor toward Sn(ii) must be sufficiently stronger than TMEDA.In order to further evaluate the decisive feature .(1) Larger amounts of distannane (2) Phosphine donor (dmpe) does not initiate dehydrogenation, although it is expected to be a potent donor towards Sn.70(3) One of the expectably strongest amine bases tested (proton sponge) reveals only poor activity.vs. DMAP).(4) Increasing nucleophilicity and basicity leads to a lowering of the activation energy barrier  efficient dehydrogenation is observed.70For bases in a comparable p2SnH2 . Moreover, existing studies on amine-catalysed dehydrogenation of organotin dihydrides R2SnH2  go along with the formation of Sn–Sn bonds to yield catenated oligomers or polymers. On account of extensive studies Neumann et al. suggested that the essential dehydrogenation processes are intermolecular and take place at the ends of growing chains H–(R2Sn)n–H without the involvement of intermediately generated free diorgano stannylenes R2Sn that condense to polymeric chains. Moreover they observed the dehydrogenation to be unaffected by addition of quinones and therefore excluded a radical chain mechanism in favour of a polar one.5To the best of our knowledge, apart from suggestions and general observations, literature does not provide conclusive evidence of the chemical processes for the dihydrogen release from R2SnH2  Neumann et al. reported an increased reaction rate when traces of tin halides (such as Ph2SnCl2) were added as cocatalyst (vide supra).10 Especially amine-base catalysed dehydrogenation of some organotin dihydrides purified by distillation was observed to be much slower or incomplete compared to crops of organotin dihydride that have not been purified by distillation.5 It was suggested that some tin halide impurities may stay in a pre-equilibrium with hydride–halide exchange that result in formation of R2Sn(H)Cl from which hydrogen is known to be readily eliminated in the presence of bases forming dichloro distannanes. However, the respective reaction rate was reported to be unaffected by the addition of pyridinium chloride, what somehow contradicts the assumption of the halide supported catalysis.14 For the formation of (Bu2ClSn)2 from Bu2Sn(H)Cl Davies et al. expected a radical chain mechanism.67In some of their studies on dehydrogenations of R31 do not indicate a pronounced acceleration due to tin halides. Moreover unlike all previous studies we observed a base-stabilized monomeric stannylene species as a final product. We assume the formation of distannane 4 to result from a subsequent reaction of the monomeric stannylene rather than a separate mechanism for the Sn–Sn bond formation.Our own observations for dehydrogenation of Ar*SnH31 catalyzed by amine bases seem plausible  bases with penta-coordinated tin are well known and crystallographically documented for organotin halides Rn4–SnXn (with n ≥ 1). However in the case of tetraorgano stannanes without electronegative substituents, indications for donor–acceptor interactions of amines with poorly Lewis acidic Sn is only found in constrained intramolecular arrangements partially leading to increased reactivities of the hydride. The poor Lewis acidity may also be seen from the optical stability of chiral stannanes and tin hydrides even in the presence of bases. On addition of some Lewis-bases triorganotin hydrides have been found to be more active hydride donors. Apart from these reactivity related observations, there is no spectroscopic evidence for self-aggregation or hyper-coordination of organotin hydrides in solution and solid state. However to the best of our knowledge no systematic studies have been made for organotin trihydrides.3Taking these facts into account and considering our own observations, two mechanistic pathways (I and II) for the dehydrogenation of Ar*SnHlausible . Both re3(DMAP) LA  a Lewis-adduct such as PhSnH3(DMAP) is found to be a minimum on the potential energy surface with the formation being exothermic , but slightly endergonic ΔGLA = +4.7 kcal mol–1. The N-donor atom is directed towards the penta-coordinated Sn centre. Computations also provided a transition state (TS-A) for the extrusion of dihydrogen from the adduct complex . Similar values for ΔGLA and ΔG‡TS-A have been computed for the corresponding intermediates and transition states when pyridine or Me3N or solvent effects applying a polarized continuum model (PCM) for benzene or THF were considered. The computed activation energy found for the dehydrogenation of Lewis adduct PhSnH3(DMAP) is comparable to the barrier height computed for the dehydrogenation of an uncoordinated terphenyltin trihydride Ar′SnH3.49In accord with the reluctance of organohydro stannanes toward aggregation and penta-coordination, in our case, NMR spectroscopy does not provide any evidence for a species such as the Lewis-adduct Ar*SnH path I, . However complex . However31 by an amine base. Proton abstraction from organotin dihydrides is known for strong bases .87 The resulting [R2SnH]– anion can serve as a source for nucleophilic tin. Formation of polystannanes was however not observed in these mixtures.87 Along with earlier suggestions that the hydrogen in organotin dihydrides reveals more electrophilic character than in organotin monohydrides, further emphasis on the electrophilic nature may be assumed in organotin trihydrides and therefore accessibility for deprotonation under milder conditions seems plausible.9 The proposed mechanism proceeds via highly polar intermediates, in agreement with the observed acceleration in more polar solvents. Computational insights [TPSS/6-31G*-def2TZVP(Sn)] into the deprotonation of PhSnH3 with NMe3 or pyridine in THF (PCM model) revealed a transition state TS-B1 with ΔG‡TS-B1 of 15.8 or 22.3 kcal mol–1 which is in reasonable agreement with the experimentally determined value.88 Within the narrow scope of valid comparisons of energetic barriers between the experimentally studied system and the chosen model system the computational results allow the consideration of the deprotonation to be involved in the reaction path.89 When a rough correction of the entropic term TΔS‡TS-B1 for the computational ΔG‡TS-B1 was applied, the obtained ΔG‡TS-B1(corr) reproduce the qualitative trend of the experimentally observed reaction rates.93 However such entropy corrections have partly been criticized only recently.94Mechanistic proposal II is a heterolytic cleavage of a proton from Ar*SnH2]– anion under formation of hydrogen via putative TS-B2 is assumed to be much quicker. In order to access experimental insight whether dihydrogen is directly generated from the proposed ion pair or if the ion pair can separate, a crossover experiment was performed. Indeed, from a 1 : 1 mixture of Ar*SnH3 and Ar*SnD31-D with DMAP formation of small amounts of HD gas was observed in 1H NMR spectra. However, firm conclusions from this observation are prevented by a slow H/D exchange equilibrium between the educts generating Ar*SnHD2 and Ar*SnH2D from which HD may also be eliminated intramolecularly. This exchange equilibrium was also confirmed for solutions without addition of DMAP.From these agreements, we propose this deprotonation step to be rate determining for the overall reaction. The subsequent protonation under hydride abstraction from the 2 and the crystallographically characterized Ar*Sn(DMAP)SnH2Ar* which is the DMAP adduct to its stannylstannylene-type isomer BH.In conclusion we presented a new approach toward the generation of terphenyltin(2SnSnH2Ar* was observed. The formation is proposed to occur via insertion of transiently formed Ar*SnH J into the Sn–H bond of Ar*SnH31 when efficient stabilization of the reactive Lewis-acidic Sn(ii) center is not provided.Moreover, it was shown that the stoichiometric ratio of DMAP base can determine the product composition. In the case of catalytic amounts of DMAP quantitative dehydrocoupling to form a diorganodistannane Ar*HC double bonds in hydrostannylenylation reactions to yield a half-sandwich complex of tin(ii), Ar*SnCp*, which was structurally characterized. In a set of experiments, including deuterated species, the activation energy as well as kinetic isotope effects and solvent dependencies of the dehydrogenation reaction were determined. Along with the results from accompanying computational studies a plausible mechanism of the reaction was proposed to include the deprotonation of the Ar*SnH3 as the rate-determining step.The generated derivatives of Ar*SnH were shown to be easily added to polar fulvenic Cii) species. This reaction may be seen as a tin organometallic equivalent to the long known reduction of PbCl4 to PbCl2 under reductive elimination of chlorine. Reductive eliminations are among the key steps in important catalytic transformations and their observation in main groups is of special interest for further development of main group catalysed transformations.The overall reaction represents a rare example for a catalytic reductive elimination from a tetravalent group 14 element to form a monomeric tin and used without further purification, i-Pr2NEt, Et2NMe and TMEDA were obtained commercially (Aldrich) and distilled from CaH2  or from n-BuLi (TMEDA) and degassed.All manipulations were carried out under argon atmosphere using standard Schlenk techniques or an MBraun Glovebox. THF, diethylether and benzene were distilled from sodium/benzophenone, toluene from sodium. Hexane and pentane were obtained from an MBRAUN solvent purification system and degassed. Benzene-95 -lithium-etherate (Ar*Li(OEt2)),95 -Sn(ii) chloride (Ar*SnCl)96 and trihydride (Ar*SnH3)51 were prepared according to modified literature procedures. Ar*SnD3 was described earlier.97 1,2,3,4-Tetramethyl fulvene was prepared according to a literature procedure.98Terphenyl-iodide (Ar*I),Elemental analysis was performed by the Institut für Anorganische Chemie, Universität Tübingen using a Vario MICRO EL analyzer. IR spectra were recorded as KBr pellets prepared in a glovebox and measured with a Bruker VERTEX 70 IR spectrometer. Detailed information of the conducted kinetic studies are given in the ESI.1, 6 and 8 were collected with a Bruker Smart APEX II diffractometer with graphite-monochromated Mo Kα radiation. The programs used were Bruker's APEX2 v2011.8-0 including SADABS for absorption correction and SAINT for structure solution, as well as the ShelXLE graphical user interface for ShelXL for structure refinement. For further refinement details see the attached .cif-files and the details provided in the ESI.X-ray data for 1H), 62.90 (13C) and 93.31 MHz (119Sn), a Bruker AvanceII+400 NMR spectrometer equipped with a 5 mm QNP (quad nucleus probe) head and operating at 400.13 (1H), 100.62 (13C) or a Bruker AVII+500 NMR spectrometer with a variable temperature set up and a 5 mm ATM probe head or a 5 mm TBO probe head and operating at 500.13 (1H), 125.76 (13C), 186.55 MHz (119Sn). Chemical shifts are reported in δ values in ppm referenced on the solvent 2H resonance frequency C6D6 , tol-d8 (1H 2.09), py-d5 . The proton and carbon signals were assigned where possible via a detailed analysis of 1H, 13C or 13C-UDEFT, 1H–1H COSY, 1H–13C HSQC, 1H–13C HMBC NMR spectra. Selected 1D-NMR spectra of the compounds and mixtures can be found in the ESI.NMR spectra were recorded with either a Bruker DRX-250 NMR spectrometer equipped with a 5 mm ATM probe head and operating at 250.13  along with w06 density fitting as well as Stuttgart–Dresden effective core potentials on tin as implemented in Gaussian. Grimme dispersion correction with Becke-Johnson damping has been taken into account using the D3BJ option implemented in Gaussian.107 Starting geometries for geometry optimizations were directly taken from the X-ray data were available (Ar*SnH3 and [Ar*SnH]2) or from manipulations on the basis of these X-ray structures (monomeric Ar*SnH). Starting geometries for the optimization of base-adducts to Ar*SnH were obtained from substitution of the donor molecule on the basis of the structure of Ar*SnH(NHC).24 Thermal corrections were obtained from frequency calculations performed for all optimized structures. Frequency calculations revealed no or a single imaginary frequency smaller than 9 cm–1, except for Ar*SnH were two small imaginary frequencies were obtained (6 and 11 cm–1).DFT calculations have been performed using the Gaussian09 Revision D.01 program.3 was chosen. Computations were carried out in Gaussian09 Revision D.01 using TPSS functional108 along with 6-31G* basis set109 for C, H and N and a def2TZVP basis set along with Stuttgart–Dresden ECP for Sn and dispersion correction as implemented in Gaussian. Solvent THF was simulated by a PCM model. A table of the computed energies at standard conditions and details on the geometry optimizations is given in the ESI.For the studies of the mechanism dehydrogenation of model compound PhSnH3  in benzene (2 mL) catalytical amounts of DMAP  was added and the solution was stirred at 70 °C for 14 days. The resulting beige solution was filtered through a syringe filter and the solvent was removed under reduced pressure to quantitatively yield Ar*H2Sn–SnH2Ar* as a colorless powder . From saturated solutions of warm benzene large colorless crystals of Ar*H2Sn–SnH2Ar* can be obtained, however these crystals were not suitable to provide high quality X-ray diffraction data. Analytical data: 1H-NMR : δ = 7.14 , 7.12–7.09 , 3.94 , 2.91 , 2.76 , 1.36 , 1.28 , 1.06 ; 13C{1H} : δ = 149.2 (ipso-CPh), 148.5 (p-Ctrip), 146.3 (o-Ctrip), 141.8 (o-CPh), 140.3 (ipso-Ctrip), 128.9 , 127.4 , 121.3(m-Ctrip), 34.8 , 30.9 , 26.0 , 24.5 , 23.6 (o-CHMe2); 119Sn–1H-coupled  δ = –393.4 . Anal. calcd for [4] C72H102Sn2: C 71.77, H 8.53; found: C 71.44, H 8.39. IR : 1875 , 560 .To a solution of Ar*SnH3  in benzene (3 mL) a solution of 4-N,N-dimethylaminopyridine (DMAP)  in benzene (3 mL) was added at room temperature. Hydrogen evolves and the increasingly yellow mixture was stirred overnight until the reaction was complete. Solvents are removed under reduced pressure and to quantitatively yield [Ar*SnH × 6(DMAP)] as a yellow powder, that can be used for any further reactions. Excessive DMAP can be removed by extraction of the residue with minimum amounts of pentane (approx. 2 × 1.5 mL) to yield [Ar*SnH × 1–1.5(DMAP)]. In solution, DMAP coordination reveals to be dynamic, therefore sharp NMR spectra of [Ar*SnH × 1–1.5(DMAP)] cannot be obtained at room temperature. From solutions with excessive DMAP (6–10 eq.) sharp 1H NMR spectra with the signals sets for Ar*SnH(DMAP) can be obtained. The NMR spectra reported reflects the signals sets with 10 eq. DMAP.To a solution of Ar*SnHAH/BH was prepared as described (vide infra) from Ar*SnH3 and Et2NMe (approx. 10 eq.) and the deep blue mixture was kept for 6 hours before DMAP (1 eq.) was added to yield a yellow solution. The solution is stirred for 15 min before all volatiles are thoroughly removed under reduced pressure to yield Ar*SnH(DMAP) (5) in 95% purity as a yellow powder. Analytical data: 1H-NMR : δ = 11.64 , 8.32  7.28 , 7.20 , 7.15 , 6.08 , 3.40 , 2.87 , 2.27 , 1.43 , 1.28 , 1.22 ; 13C{1H} : δ = 167.4 (ipso-CPh), 154.0 (p-CDMAP), 150.6 (o-CDMAP), 147.5 (o-Ctrip), 147.5 (p-Ctrip), 147.1 (o-CPh), 140.5 (ipso-Ctrip), 128.9 (m-CPh), 125.2 , 120.9 (m-Ctrip), 106.8 (m-CDMAP), 38.2 (NMe2), 34.7 (p-CHMe2), 31.0 (o-CHMe2), 26.1 (o-CHMe2), 24.5 , 23.8 (o-CHMe2); 119Sn–1H-coupled  δ = 224.9 . IR : likely superimposed: see ESI.5 failed so far, we have not been able to provide a sample suitable for elemental analysis.A solution of 3 (75 mg) and DMAP (91.1 mg) a mixture of solid [Ar*SnH × 6(DMAP)] is prepared as described above. The yellow solid is extracted with cool (ca. 0 °C) pentane (2 × 0.8 mL) and the brightly yellow extracts were concentrated to approx. 1 mL and stored at –40 °C for two days. The residual white powder corresponds to approx. 80% of the DMAP used. From the cooled extracts further amounts of DMAP crystallize as fine colorless needles and the cool supernatant yellow solution is separated with a syringe. When warmed to ambient temperature the solution turns green. Bright yellow crystals of Ar*Sn(DMAP)–SnH2Ar* (6)  suitable for X-ray diffraction were obtained from this solution after a few days at –40 °C. It seems that 6 can only be isolated in the solid state since in solution, it reveals to be in an equilibrium with H and 5. In VT-NMR experiments at lower temperatures sharp resonances were observed in the temperature range from –30 to –50 °C allowing the identification of 6 in mixtures with 5 and H. The resonances reported here correspond to the characteristic signal sets that were assigned to 6 in the spectra of the mixtures, however a thorough assignment of all resonances is circumvented due to overlap with similar ligand related signals for 5 and H. The complete spectrum of the mixture can be found in the ESI.1H-NMR : δ = 5.55 , 5.47 ; 119Sn–1H-coupled  δ = 374.4 ), –248.0 ; anal. calcd for [6] C79H110N2Sn2: C 71.60, H 8.37, N 2.11; found: C 71.77, H 8.15, N 2.17. IR : 1763 , 600 . N. B. Due to the equilibrium the resulting mixture of similar overlapping compound signals prevents a meaningful assignment of the 13C NMR signals.From Ar*SnH3  in d5-pyridine (0.5 mL). Upon heating the cloudy solid instantly goes into solution and the mixture is kept at 95 °C for 4 h with obvious hydrogen evolution to yield a clear bright yellow solution of Ar*SnH(py) with approx. 4% of distannane (4) being formed as side-product. Analytical data: 1H-NMR : δ = 12.13  8.76 , 7.61 , 7.50 , 7.32 , 7.25 overlaying with solvent signal , 3.37 , 3.00 , 1.38 , 1.37 , 1.20 .13C{1H} : δ = 167.4 (ipso-CPh), 150.2 (py-d5), 148.4 (p-Ctrip), 147.7 (o-CPh), 147.4 (o-Ctrip), 140.0 (ipso-Ctrip), 135.8 (py-d5), 129.2 (m-CPh), 125.9 , 123.8 (py-d5), 121.4 (m-Ctrip), 34.8 (p-CHMe2), 31.2 (o-CHMe2), 26.3 (o-CHMe2), 24.7 , 23.9 (o-CHMe2) 119Sn–1H-coupled  δ = 283 , a second minor signal (approx. 30%) is observed at δ = 279 ppm. 1H NMR does not contain signal sets for a second Sn–H compound in the solution. According to chemical trapping experiments, this signal corresponds to an isomeric form of Ar*SnH(py) (7), since it completely vanishes upon reaction with 1,2,3,4-tetramethyl fulvene forming only one product Ar*SnCp* 8.In a NMR experiment, a J. Young-NMR tube is charged with a suspension of Ar*SnH3  and DMAP  in benzene (3 mL) is stirred at ambient temperature for 8 h. A solution of 1,2,3,4-tetramethyl fulvene  in benzene (0.5 mL) is added and the solution is stirred for 30 min before all volatiles are removed in vacuo. The yellow residue is extracted with cool pentane  and the bright yellow extract is stored at –40 °C for a few hours to furtherly crystallize residual DMAP as colorless plates. The cool supernatant yellow solution is separated via syringe and the volatiles are removed to obtain Ar*SnCp* (8) as a yellow powder (95% purity) . Crystals suitable for X-ray diffraction were obtained from saturated solutions in hexane or pentane at –40 °C.A solution of Ar*SnH3  and Et2NMe  in benzene (2 mL) is stirred at ambient temperature for 6 h. Successively, a solution of 1,2,3,4-tetramethyl fulvene  in benzene (0.5 mL) and 0.1 mL dry pyridine are added to the deep blue solution. On addition of pyridine the mixture immediately turns bright yellow. The solution is stirred for 30 min before all volatiles are removed in vacuo to obtain Ar*SnCp* (8) as a yellow powder (>95% purity) . Analytical data: 1H-NMR : 7.26 , 2.73–2.17 , 3.13 , 2.90 , 1.76 , 1.47 , 1.33 , 1.22 ; 13C{1H} : δ = 195.7 (ipso-CPh), 148.6 (p-Ctrip), 147.0 (o-Ctrip), 144.9 (o-CPh), 138.1 (ipso-Ctrip), 131.2 (m-CPh), 125.8 (p-CPh), 121.6 (m-Ctrip), 117.8 (Cp*–C5), 35.0 (p-CHMe2), 31.05 (o-CHMe2), 26.8 (o-CHMe2), 24.4 (p-CHMe2), 23.1 (o-CHMe2), 10.4 (C5–CH3); 119Sn{1H}  δ = –26 (s). Anal. calcd for [8] C46H64Sn: C 75.10, H 8.77; found: C 75.17, H 8.61.A solution of Ar*SnH


Endocrine disrupting chemicals (EDCs) can mimic natural hormone to interact with receptors in the endocrine system and thus disrupt the functions of the endocrine system, raising concerns on the public health. In addition to disruption of the endocrine system, some EDCs have been found associated with many diseases such as breast cancer, prostate cancer, infertility, asthma, stroke, Alzheimer’s disease, obesity, and diabetes mellitus. EDCs that binding androgen receptor have been reported associated with diabetes mellitus in in vitro, animal, and clinical studies. In this review, we summarize the structural basis and interactions between androgen receptor and EDCs as well as the associations of various types of diabetes mellitus with the EDCs mediated through androgen receptor binding. We also discuss the perspective research for further understanding the impact and mechanisms of EDCs on the risk of diabetes mellitus. Metabolic diseases have dramatically increased over the last several decades. Diabetes mellitus are described as a complex and serious condition of metabolic disease associated with abnormally high levels of blood sugar (glucose) resulting from deficiency of insulin secretion and/or action. Generally, there are two types of diabetes mellitus. Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which the immune system is activated to destroy the cells in the pancreas which produce insulin. Type 2 diabetes mellitus (T2DM) is a progressive condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas . In 2013p-dioxin, diethylhexyl phthalate and polychlorinated biphenyl have been proven to induce insulin resistance in cellular and animal models [The mechanisms of diabetes mellitus have not been fully understood. Several pathogenic processes are involved in the development of diabetes mellitus. Type 1 diabetes mellitus is resulting from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action . Type 2 l models ,11, leadIt has been reported that sex-specific activation of androgen receptor (AR) in the hypothalamus, skeletal muscle, liver, adipose tissue and pancreatic islet β cells accounts for maintenance or disruption in energy metabolism and glucose homeostasis . Men witNuclear receptors are the ligand-regulated transcriptional factors that play a key role in the development and homeostasis, reproductive and metabolic disorders like diabetes mellitus, obesity, and cancer . Hence, The estrogen receptor is one of the important endocrine targets involved in cancer and other diseases ,20. ER hIn addition, EDCs have been reported to promote adipogenesis through modulation of peroxisome proliferator receptors (PPARs), which act as a transcription factors and control the expression of genes involved in lipid, glucose and cholesterol metabolism . Three mThe hypothalamic pituitary adrenal axis controls the production of glucocorticoid hormones through the adrenal cortex. Glucocorticoid binds in the active site of GRs and MRs in different target tissues . Excess Aldosterone is the primary endogenous member of the mineralocorticoid hormones. Aldosterone acts on the MR to enhance the reabsorption and excretion of sodium and potassium in the kidney. The function of MR is to maintain blood pressure as well as electrolyte homeostasis through the distal nephron . AldosteHigh level of progesterone, an endogenous steroid hormone, leads to development of glucose abnormalities in the second trimester of pregnancy . Hence, The androgen receptor plays an important role in male sexual development and regulates gene expression in various tissues. Lack of testosterone in men could lead to development of T2DM and hypogonadism ,58. The The androgen receptor is a soluble nuclear receptor protein. The human AR gene is located on X-chromosome and contains 2757 nucleotides that encode the AR protein ,60,61. TThe mechanism of androgenic activity consists of multiple steps that are illustrated in Androgen is a steroid derived sex hormone. It plays a major physiological role in male. Testosterone and DHT are the well-known and important androgens. Testosterone is the major circulating androgen and is synthesized from cholesterol in several steps. Initially, steroidogenic acute regulatory (StAR) protein transfers cholesterol from outer mitochondrial membrane into inner membrane. Subsequently, cholesterol side-chain cleavage (P450scc) enzyme cleaves the side chain of cholesterol . This coThe 5α-reductase catalyzes the conversion of testosterone into DHT. Dehydrotestosterone is a metabolic product that is more active than testosterone . The andThere are increasing evidences that androgen plays a major role in prostate cancer. The androgen receptor is mainly activated by androgens (agonist) such as testosterone, DHT, synthetic androgen etc. Agonist binding in the LBP (active site) of AR-LBD holds H12 to maintain the active conformation of AR . HoweverAntiandrogens or AR antagonists are a competitive binder for androgens in AR. They are synthetic compounds which bind in the androgen binding site of AR. An antiandrogen inhibits AR activity by blocking binding of androgen in the active site of AR. Binding of an antagonist in the active site of mutated AR showed a similar structural changes and binding interaction as an agonist binding in wild type AR. Due to the absence of wild type AR-LBD with antagonist crystal structure, there is no strong evidence to propose the binding orientation of antagonists in AR . BindingBinding of androgens to AR converts inactive AR to its active form. The active AR regulates various target genes by interacting with different coregulatory proteins. There are growing evidences to support the role of androgens in diabetes mellitus . The defAR associated diseases and chemicals that interact with AR were downloaded from Comparative Toxicogenomics Database . Comparative analysis on the diseases associated with AR and the chemicals interacted with AR found that 13 androgenic chemicals are associated with diabetes mellitus. The 13 androgenic compounds were clustered into five groups based on the medical subject headings (MESH) ID . The 2D Cluster 1 has organochlorine insecticides and pesticides that are potential EDCs in the environment. These chemicals disrupt the function of AR by mimicking its natural hormones such as testosterone. Few pesticides and their metabolites bind in the ligand binding pocket of AR, altering AR normal functions. These chemicals act as antagonists in vitro. Fang et al. reported the relative binding affinity of 2,4,5-trichlorophenoxyacetic acid, aldrin, and heptachlor were 0.0007, 0.0096, and 0.0133, respectively, in the competitive binding assay . 2,4,5-TIncreasing use of pesticides in the environment has been found associated with the risk of diabetes mellitus. Long term exposure of pesticides can increase the risk of diabetes mellitus ,93. Orga“Diabetes mellitus experimental” is a descriptor in the National Library of Medicine’s controlled vocabulary thesaurus, MeSH . It is designated as “Diabetes mellitus induced experimentally by administration of various diabetogenic agents or by pancreatectomy”. Capsaicin and clioquinol play a role in diabetes mellitus through various pathways.Capsaicin is a non-pungent capsaicin analog which modifies or alters the secretion of insulin . It incr50 value of 5900 nM. Some BPA derivatives also showed antagonistic effect towards AR [Bisphenol A (BPA), a diphenylmethane derivative, is an antagonist for AR. Bisphenol A is one of the endocrine disruptors which bind in the ligand binding pocket of AR and alter its functions. Bisphenol A had shown AR-antagonistic activity in reporter gene assay with an ICwards AR . Calcitrwards AR .Type 1 diabetes mellitus  is characterized by deficient insulin production and requires daily administration of insulin . It accoThe chemicals in Cluster 3 are androgenic and play an important role in T1DM ,99. BispBisphenol A is a polycarbonate plastics present in many consumer products like water bottles and food. Bisphenol A is androgenic and was found associated with both T1DM  and T2DMType 2 diabetes mellitus  results from the body’s ineffective use of insulin. Type 2 diabetes mellitus, a common disease, accounts for 90–95% of the people with diabetes mellitus around the world and is estimated to affect 380 million people worldwide by 2025 . Type 2 Exposure to BPA leads to insulin resistance which results in T2DM through the highly expressed pancreatic β cells . BisphenIn addition to diabetes mellitus experimental and T2DM, resveratrol was also found associated with diabetic nephropathies (DN). Estradiol, a steroid estrogen, had a relative binding affinity of 0.758 in the AR competitive assay . EstradiDiabetic nephropathy is a well-described complication of diabetes mellitus and is one of the microvascular complications of the kidney commonly due to T1DM, and occasionally from T2DM. Diabetic nephropathy is characterized by glomerular hypertrophy, proteinuria, decreased glomerular filtration, and renal fibrosis resulting in the loss of renal function . DiabetiEstradiol decreases activity of reticular activating system (RAS) system by reducing renin levels and increasing angiotensin II type 2 receptors (AT2Rs) which are associated with DN . LowerinDiabetes mellitus is recognized as one of the risk factors in cancer development. Endocrine disrupting chemicals mediated through AR have been found associated with diabetes mellitus. However, understanding of the mechanisms of androgenic EDCs causing diabetes mellitus is limited. Studies to ascertain the causality of diabetes mellitus by androgenic EDCs are expected in the future. As only few of the known androgenic EDCs have been assessed for their risks to diabetes mellitus in clinical and animal studies, the risk of diabetes mellitus for the remaining known androgenic EDCs should be evaluated to better protect the public health.


In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR) in the mammalian neuromuscular junction (NMJ). Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse  cross the extracellular cleft to generate signals in target metabotropic receptors. Thus, the integrated interpretation of the complementary function of all these receptors is needed. We previously studied, in the NMJ, the links of AR with mAChR and the neurotrophin receptor TrkB in the control of synapse elimination and transmitter release. We conclude that AR cooperate with these receptors through synergistic and antagonistic effects in the developmental synapse elimination process. In the adult NMJ, this cooperation is manifested so as that the functional integrity of a given receptor group depends on the other receptors operating normally . These observations underlie the relevance of AR in the NMJ function. In addition to the main neurotransmitter-receptor signal, several signaling pathways coordinate the pre- and postsynaptic cells and associated glia in the tripartite synapses in accordance with functional demands. In the NMJ, presynaptic mAChRs directly couple ACh secretion to the regulation of the release mechanism itself . MoreoveStudies in the early 1970s In the last few years, we have studied the presence and involvement of AR in the synaptogenesis and transmitter release in the developing and mature mammalian NMJ ,b, 2017.1R and A2AR subtypes) contribute to the developmental synapse elimination process, helping to define the winner of the competition between axon terminals. In the adult, AR help to modulate transmitter release by limiting spontaneous quantal leak of ACh and preserve synaptic function by reducing depression during repetitive activity. To realize these functions, several synergistic and antagonistic relations exist between AR and, at least, the mAChR subtypes  and the TrkB receptor. These observations underlie the relevance of AR in the NMJ function.Our results indicate that during NMJ synaptogenesis, AR  and despite the fact that there was some uncertainty about how they were distributed in the cells of the paradigmatic NMJ  in P6 and P30 NMJ . Moreover, localization of A2BR, and A3R has been determined in P30 NMJ. By triple labeling of NMJ we stained each one of these protein receptors in green fluorescence together with Syntaxin or S-100 (blue fluorescence) and nAChR (red fluorescence) and we saw that the molecules were present. However, since the components of the NMJ  are juxtaposed, it is not always easy to locate the proteins with precision. Thus, in some cases, to better determine A1R and A2AR localization, we used plastic embedded semithin cross-sections as a tool for high-resolution together with the triple-labeling immunofluorescence analysis. Briefly, after conventional immunohistochemistry the samples were dehydrated with increasing concentrations of ethanol and acetone, the tissue fragments were embedded in Spurr’s resin in transverse orientation and sections (0.5–0.7 μm thick) were obtained  and the interpretation of the results here is not a full representation of the AR physiology.Immunofluorescence staining coupled with confocal microscopy analysis was performed to determine the localization of Aobtained . Images the NMJs , 2014. TDuring the nervous system development there is an overwhelming production of synapses (that may promote connectiviy), followed by an activity-dependent reduction of them. Hebbian competition between axons refines connectivity and increases specificity . In newbThe postsynaptic cell and the terminal Schwann cells may be intermediary in axonal competition. A decrement in polyneuronal innervation occurs at a time when relatively little loss of the nAChR postsynaptic receptors was observed . However1R and A2AR), which monitor both nerve- and muscle-derived adenosine release during the complex period of axonal elimination around P5-P9 . At P7, after the inhibition with 8SPT of the AR, we observed an acceleration of the axonal elimination on the NMJ indicating that, at this point of development, the role of AR is to delay axonal loss . We also analyzed axonal loss after selectively blocking A1R with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or A2AR with 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo  triazolopyrimidin-5-amine (SCH-58261) , the purinergic function accelerates axonal loss to the maximum rate. Therefore, an initial delay in axonal loss at P7 (an A1R- and A2AR-mediated effect which can be reinforced by exogenously added adenosine) is followed by an A1R- and A2AR-mediated tonic acceleration of axonal loss at P9  suggesting that axonal competition and loss are differentially modulated  (from now YFP) and C57BL/J6 mice. To the flat and accessible mouse LAL muscle, we subcutaneously applied the unselective AR inhibitor 8-(p-sulfophenyl) theophylline (8SPT) and the agonist adenosine between P5-P15  ,b. Resulodulated .Figure 2B). Based on criteria from previous studies on developing mammalian NMJ . However, at P9 we found that MS2clusters were increased while the MS1 and MS3 ones decreased , which indicates a delay in the transition from MS2 to MS3. At P15  the postsynaptic maturation is partially retained at the MS3 stage. Thus, AR are able to accelerate maturation during the P7–P15 period. Interestingly, the agonist adenosine does not unambiguously change the cluster maturation indicating that the tonic effect of the AR evidenced by using 8SPT is close to their maximum  clusters in the postsynaptic site  reduces it (2AR agonist 2-p-(2-Carboxyethyl)- phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate, 1 μM (CGS-21680) increases it (1R reduces release (in high Mg2+ and curare blockade) when the NMJ is already weakened and because of that, the meaning of this regulation seems unclear  and A2AR-selective agonists and antagonists  -2-[4-phenoxy]acetamide, 100 nM) and the A3R-selective antagonist MRS1334 -3,5-pyridinedicarboxylic acid 3-ethyl-5-[(3nitrophenyl)methyl] ester, 100 nM). We unexpectedly found that A2BR and A3R neither had any effect on depression (just as the A1R and A2AR selective antagonists). Thus, we concluded that two or more AR are necessary to protect against depression  . Howeverrequency . In addirequency . Surprislaborate . In perspression .Figure 3).In summary, these findings confirmed that in basal conditions AR are not coupled to any immediate modulation of evoked neurotransmission. However, these receptors are still crucial to preserve resources by avoiding the leak of spontaneous quantal ACh, an action which is probably implicated in their protective role against synaptic depression after repetitive activity ,  described above, we investigated the involvement of individual mAChR M1-, M2-, and M4-subtypes and the TrkB receptor .In relation with the synapse elimination process during development, in addition to the role of AR subtypes . A1, M1, and TrkB are coupled to stimulate PKC whereas A2A, M2, and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity in some nerve endings may play an important role in promoting developmental NMJ maturation.Thus, both AR are necessary to modulate synapse elimination and several synergistic and antagonistic links are observed between all receptors, which regulate axonal loss  produce minor changes in spontaneous quantal output  whereas other receptors  induce major changes in evoked release. Thus, each receptor regulates a given combination of spontaneous, evoked and activity-dependent ACh release. As it has been mentioned before, AR preserve resources by reducing spontaneous leak of neurotransmitter (an A1R effect) and normalize the synapse function because stimulation with adenosine reduces the magnitude of depression during repetitive activity. mAChR stabilize the spontaneous quantal output of ACh and also preserve the synapse function by decreasing evoked release (mainly an M2 action) and reducing depression. A role for the TrkB receptor is to stabilize the spontaneous quantal leak of ACh but it mainly potentiates evoked release and synaptic potentials . However, the same effect is observed in the other way around: a previous blockade of mAChR does not allow applied adenosine to change the above described effect on ACh release in our conditions.We also studied the consecutive incubation with two inhibitors affecting two different receptors to see their collaboration in neurotransmission. Adenosine outflow from nerve endings may, through Apathways . We obsee mAChRs  .Finally, it has also been reported that adenosine acting through A binding . Thus, AAutoreceptors subtypes are present in the motor nerve endings in the NMJ. During development, AR modulate the competition between axon terminals, helping to define the winner and the losers . To accoThe mice were cared for in accordance with the guidelines of the European Community’s Council Directive of November 24, 1986 (86/609/EEC) for the humane treatment of laboratory animals. All experiments on animals have been reviewed and approved by the Animal Research Committee of the Universitat Rovira i Virgili (Reference number: 0233).LN, EH, AS-O, VC-M, LJ-B, MS, and MT: data collection, quantitative analysis, literature search, data interpretation, and graphic design. NG and ML: statistics. JT, NG, and ML: conception and design, literature search, data interpretation, and manuscript preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CS and handling Editor declared their shared affiliation.


The aim of the present single-case study was to investigate the effect of 6 weeks' kettlebell training on the neuromuscular risk profile for ACL injury in a high-risk athlete returning to sport after ACL reconstruction. A female elite soccer player (age 21 years) with no previous history of ACL injury went through neuromuscular screening as measured by EMG preactivity of vastus lateralis and semitendinosus during a standardized sidecutting maneuver. Subsequently, the player experienced a noncontact ACL injury. The player was screened again following postreconstruction rehabilitation, then underwent 6-week kettlebell training, and was subsequently screened again at 6-week follow-up. Prior to and after postreconstruction rehabilitation the player demonstrated a neuromuscular profile during sidecutting known to increase the risk for noncontact ACL injury, that is, reduced EMG preactivity for semitendinosus and elevated EMG preactivity for vastus lateralis. Subsequently, the 6-week kettlebell training increased semitendinosus muscle preactivity during sidecutting by 38 percentage points to a level equivalent to a neuromuscular low-risk profile. An ACL rehabilitated female athlete with a high-risk neuromuscular profile changed to low-risk in response to 6 weeks of kettlebell training. Thus, short-term kettlebell exercise with documented high levels of medial hamstring activation was found to transfer into high medial hamstring preactivation during a sidecutting maneuver. Anterior cruciate ligament (ACL) injuries in sports are of increasing concern for physicians and scientists worldwide . In Unit after being tested in our laboratory for neuromuscular performance during soccer relevant movements, including a sidecutting manoeuver. At the time of her ACL injury, we had identified a “high-risk” zone [In the present case study, we report findings obtained in a 21-year-old female elite soccer player , who sustained a noncontact ACL injury 3 yearssk” zone  for noncsk” zone , that isThe aim of the present case study was to describe the effect of 6 weeks' kettlebell training on the neuromuscular profile for noncontact ACL injury during sidecutting in a high-risk elite athlete returning to sport after ACL reconstruction.August 2006. A 21-year-old female soccer player competing at elite level (te level  and withMay 2009. The player sustains a documented (video recorded) noncontact ACL injury in the right knee during match play. Retrospectively examined, the initial test (2006) revealed that the female soccer player, in her uninjured state, displayed a high-risk profile during sidecutting consistent with the study reports by Zebis et al. (2009) [. (2009) . June 2009. Surgical ACL reconstruction is performed using a semitendinosus-gracilis autograft. April 2010. After 10 months of standardized rehabilitation (more details provided below), the player is deemed fully rehabilitated by medical professionals to return to preinjury sports activities, and the player returns to soccer at elite level. May 2010. The player is involved in elite soccer at her preinjury level  on vastus lateralis (VL), biceps femoris (BF), and semitendinosus (ST) muscles according to recommended standard procedures . For detDuring later offline analysis all EMG signals were high-pass filtered at a 5 Hz cutoff frequency (4th-order zero-lag Butterworth filter) and subsequently smoothed by a symmetrical moving RMS filter of 30 ms . Mean RMCMJ measurements were performed on a force plate . Countermovement jumping was performed with the hands placed at the hip (akimbo), and maximal jump height was calculated by time-integration (0.001 time constant) of vertical ground reaction force as previously described by Caserotti et al. (2001) .A standardized rehabilitation program, using generally accepted progression criteria was followed . The rehIn the first 12 weeks of rehabilitation, seated knee extension, squat on one leg, squat on two legs, heel raise, and standing on one leg were part of the training program, all exercises performed in a slow controlled manner. These exercises have previously been evaluated by EMG recording in ACL patients, 5 weeks after ACL reconstruction, demonstrating hamstring muscles activity levels corresponding to 19%–68% of MVC EMG . The balA detailed description of the first 12 weeks of rehabilitation is presented in After 12 weeks of postoperative rehabilitation, strength training was progressively increased and open kinetic chain exercise, that is, loaded knee extension in machine, as well as free-weight barbell squat was included in the rehabilitation program. The majority of strength training exercises in the rehabilitation program were aimed at targeting the quadriceps muscles, with the hamstring muscles contracting actively as antagonists (knee extension) or synergists (hip extension). In a previous study, relatively low levels of ST EMG coactivation were observed during isolated knee extension exercise, free-weight squat, and seated leg press (9% to 22% of max EMG) in young healthy males . FurtherUpon completion of the postoperative rehabilitation phase, the player was tested according to the recommendations of return-to-play . The plaSince neuromuscular testing revealed that the players ST activation deficit persisted to exist during sidecutting after completion of the standard rehabilitation protocol, it was decided that the player should perform 6 weeks of additional training that was designed to preferentially target the medial hamstring muscle (more details given below). In this context, the kettlebell swing exercise has been reported to be particularly effective to targeting the ST muscle, demonstrating markedly higher EMG activity levels than ballistic one-legged balance/coordination exercises . The ketThe player performed kettlebell swings using a 16 kg kettlebell according to the strength level of the subject and progressed later to 20 kg at the end of the intervention period. The kettlebell weight was chosen to match a weight where the subject was able to swing 20 times using proper technique. In this order, the kettlebell exercise has been shown to preferentially activate the medial hamstring muscle and at high EMG activity levels . The plaIn total, the player performed 10 training sessions during the 6-week period. Each training session consisted of 3–5 sets, with each single set corresponding to 20 swings and 20 seconds' pause in a 2-minute time interval. In sessions 1–4, kettlebell swings were performed using a 16 kg kettlebell. In sessions 5–10, kettlebell swings were performed with a 20 kg kettlebell.Prior to ACL injury the player demonstrated a neuromuscular pattern during sidecutting known to increase the risk for noncontact ACL injury, that is, reduced EMG preactivity for the ST muscle  the player was deemed ready to return to play by the medical staff . However, the player demonstrated a persisting pattern of high-risk neuromuscular activity during the sidecutting maneuver, characterized by reduced ST preactivity  muscle activity, for which reason the kettlebell exercise was chosen. Notably, six weeks of kettlebell training was effective for changing the neuromuscular profile during sidecutting from high- to low-risk behavior, due to an increased ST EMG preactivity during the sidecutting maneuver.Excessive dynamic knee joint valgus moment during drop jumping has previously been identified to predispose for ACL injury . The medWe have previously reported that a multiexercise neuromuscular training program known to reduce the incidence of ACL injury among female elite athletes  may achiThe intervention strategy with six weeks of kettlebell training changed the neuromuscular profile from high- to low-risk . Thus, tAs seen in the present study participant, ACL ruptures typically are reconstructed by using the ST tendon as an autograft . A folloIn conclusion, this case describes an elite female soccer player who, after sustaining a noncontact ACL injury, having the ACL reconstructed and fulfilling 10 months of intensive ACL rehabilitation, still had a high-risk neuromuscular profile as she had preinjury. After only 6 weeks of kettlebell training, the neuromuscular pattern during sidecutting reversed from high- to low-risk. Thus, this exercise modality might be an important supplement to the standardized rehabilitation among patients aiming to return to sports activities. Future large-scale prospective studies should confirm whether the present findings can be used in the primary and secondary prevention of noncontact ACL injuries.


It induces sustained β1-adrenergic receptor (β1-AR) activation which leads to heart failure (HF), but the mechanism is as yet unclear. In order to investigate the mechanisms causing β1-AR non-desensitization, we studied the beating frequency of the neonatal rat cardiomyocytes (NRCMs) under different conditions  for one group and β1-AA for the other) and established three dynamic models in order to best describe the true relationships shown in medical experiments; one model used a control group of healthy rats; then in HF rats one focused on conformation changes in β1-AR; the other examined interaction between β1-AR and β2-adrenergic receptors (β2-AR). Comparing the experimental data and corresponding Akaike information criterion (AIC) values, we concluded that the interaction model was the most likely mechanism. We used mathematical methods to explore the mechanism for the development of heart failure and to find potential targets for prevention and treatment. The aim of the paper was to provide a strong theoretical basis for the clinical development of personalized treatment programs. We also carried out sensitivity analysis of the initial concentration β1-AA and found that they had a noticeable effect on the fitting results.High titer of  We have known that β1-AA and ISO compete for different binding sites of β1-AR, which belongs to the competitive inhibition in different positions of β1-AR (0) = [I0] = 1 × 10−7mol/L, [B1](0) = [B10] = 2.3 × 10−9mol/L, [B1′I](0) = 0, [B1′](0) = 0, and [P](0) = 0.(of β1-AR . Assumin3) The Interaction Model. In the preliminary study, β1-AR and β2-AR form heterodimer through the C-terminal (0) = [I0] = 1 × 10−7mol/L, [B1B2](0) = 1.8 × 10−9mol/L, [B1IB2](0) = 0, [(B1I)′](0) = 0, [B1′](0) = 0, [B2′](0) = 0, and [P](0) = 0., an, an2), aAB]pred − [AB]data at all time [AB]data got measured, where for simplicity we use [AB] to denote the concentrations of the intermediate products LB1, B1′I, and B1IB2 in the three models, respectively . We also denote the total squared summation by S. Obviously S is a function of all the parameters that require fitting. Given a set of parameters, second order Runge-Kutta method gives the value of [AB]pred and thus S. We use steepest descent method to find the minimum of S. In this process, the gradient of S over all parameters is calculated numerically. For example, for positive parameter ki, e − 6, and the time step in the Runge-Kutta method is chosen to be 0.01 min.Second order Runge-Kutta method is used to solve the ODE systems obtained in our models. Our parameter fitting is an optimization process, which minimizes the squared summation of [AB]. Instead, we assumed that the measured data is proportional to the concentration of [AB]. In other words, we introduce an extra parameter λ, and [AB]data = λTdata, where Tdata is the measured data in the tables. In the optimization process, we trait λ in the same way we trait other parameters. And λ is also get fitted. Combining We use the measured values in Next, we analyze the fitting of the graphs and the prediction of the different time points, as shown in Figures 6min to 60 mins, in which the points are experimentally measured and the curve is the solution of dynamical control group model of [LB1]. And the fitting curve finally declined which reflects the fact that β1-AR desensitizes when reacting with ISO in healthy rats. However, the situation was quite different with HF rats.mins to 120 mins. It predicts that [LB1] continues to decrease, eventually tends to zero, and becomes stable, which clearly showed the mechanism of β1-AR desensitization.min to 60 mins, in which the points are experimentally measured and the curve is the solution of dynamical conformation changes model of [B1′I].mins to 120 mins. The [B1′I] curve eventually stabilized in (b), which clearly showed the mechanism of β1-AR non-desensitization.min to 60 mins, in which the points are experimentally measured, the curve is the solution of dynamical interaction model of [B1IB2], and the fitting curve finally stabilized.mins to 120 mins. The upward trend of the [B1IB2] curve reflects the effects of β1-AA and β2-AR on the non-desensitization of the β1-AR.Then, we analyze the reaction speeds and As can be seen from Akaike's information criterion  when the initial concentrations of β1-AA are 1 × 10−9mol/L, 1 × 10−8mol/L, and 1 × 10−6mol/L in 10 minutes, while the concentration of B1B2 remains unchanged at 1.8 × 10−9mol/L. And we can see that when the concentration of β1-AA is 1 × 10−9mol/L, the fitting result is the worst, followed by 1 × 10−6mol/L and 1 × 10−8mol/L. As can be seen from β1-AA is 1 × 10−7mol/L, the fitting result is the best. Therefore, the optimum concentration of mice monoclonal β1-AA leading to the NRCMs beating frequency was 0.1 μM (detected from 1 nM to 1 μM).β1-AR and β2-AR both contribute to the HF progression in rats and the interaction has the greater impact on it. In our study, for the first time, the model block diagrams described the causation of HF. By comparing the experimental group models with the control group model and then calculating the AICc, we concluded that the interaction model between β1-AR and β2-AR was the optimal model, which leads to the important role of β2-AR in the progression of HF. β2-AR and β1-AR connect together and participate in a reaction, which then causes conformation changes in receptor β1-AR. This results in endocytosis inhibition, which ultimately leads to β1-AR non-desensitization and HF. Thus, β2-AR is an important consideration in guiding the treatment of HF.We analyzed the two types of mechanisms that cause HF; it can be concluded that conformation changes and interactions between β1-AR and β2-AR could form heterodimers, although they also found that the autoantibody β1-AA did not bind to β2-AR [β1-AA could inhibit heterodimerization of β1/β2-AR, observing laboratory experiments on animals at Capital Medical University. Therefore, we speculated that β1-AA might indirectly affect the β2-AR- C-terminal conformation and interfere with heterodimerization of β1/β2-AR. This would lead to β1-AR endocytosis inhibition, to continuous signal activation, and ultimately to heart failure.Previous studies have found that to β2-AR . We founβ1-AR and β2-AR was found to be the trigger mechanism of heart failure progression, receptor β2-AR should be further studied to determine if it could play a role in heart failure treatment. In the presence of β1-AA-positive heart failure, β2-AR can be used as a drug and therapeutic target to improve the interaction between β1-AR and β2-AR, thereby decreasing the risk of further heart failure.Because the interaction between


Agriculture reflects One Health principals, with the job of the farmer being to sustainably balance human, animal, and soil health. It is imperative to include an agricultural perspective when addressing antibiotic resistance (AR) from a One Health perspective, as the farmers, ranchers, and agricultural professionals have an intimate working knowledge of these complex systems, and they will be on the front lines of implementing on-farm control measures. Currently, communication across the One Health triad  regarding agricultural AR is hindered by ambiguous language, complicated by cultural and linguistic differences that can lead to the conclusion that the other participant is not aware of the facts, or has ulterior motives. This work explores and identifies the language and vocabulary of AR in the context of supporting strategic short- and long-term problem solving in a One Health context. Different conclusions would likely be drawn if tet(B) were used to assess resistance compared to tet(D)  (Knapp et al. Unlike assessments done in animals (Dorado-García et al. In addition to identifying terminology that has multiple definitions across the One Health partners, it is also useful to acknowledge and articulate the outcome of interest in environmental AR discussions. For example, given that AR occurs naturally in soil, and as a result of historical and current anthropogenic activities, does source of the target matter? The answer to this question depends on the outcome of interest. From the perspective of reducing risk, and reducing the occurrence of untreatable infections in humans and animals, the answer is no. Regardless of how the AR bacteria or AR genes got into the agroecosystem—whether naturally occurring or the result of anthropogenic activities—the goal is to limit their transfer out of the system. Knowing the background and baseline levels of resistance is important for measuring the impact of management and mitigation practices, but it is not mandatory to source-track individual bacteria or genes. In contrast, when assessing agricultural AR risk from a regulatory perspective, it is critical to distinguish between AR bacteria and AR genes that are the result of current anthropogenic activities, from AR bacteria and AR genes that occur naturally, or that were part of the baseline resistance on a farm. Beginning discussions by clarifying goals is another technique that can improve One Health teams.Complexities of the agroecosystem environment continue to confound efforts to define risk associated with AR across the farm to table continuum. Continuing efforts to harmonize the lexicon and to frame risk and define relevant outcomes across the branches of One Health professionals will inform and strengthen One Health efforts.