Polymorph selection by continuous crystallization

This article is motivated by a remarkable observation reported recently by Myerson, Trout, and co‐workers that continuous crystallization is capable of producing metastable polymorphs in stable steady‐state operation. We explain why this phenomenon occurs and give simple design rules for reproducing it in other polymorphic systems. A linear stability analysis gives simple functions of parameters for which one can continuously produce thermodynamically metastable products based only on the relative polymorph dynamics. We demonstrate agreement with two sets of experimental data; L‐glutamic acid grown from aqueous solution and p‐aminobenzoic acid also grown from aqueous solution. For many polymorphic compounds, engineering a process to produce a desired polymorph is as simple as finding a reasonable operating point for the continuous mixed‐suspension mixed‐product removal crystallization process (temperature, residence time, initial supersaturation, etc.) according to the rules reported in this article. © 2016 American Institute of Chemical Engineers AIChE J, 62: 3505–3514, 2016     

A tribute to professor Roger Sargent: Intellectual leader of process systems engineering

This article and this issue of the AIChE Journal, is a tribute to Professor Roger Sargent who, as pioneer and intellectual leader of process systems engineering, has had a profound impact on the discipline of chemical engineering. Spanning more than five decades, his work has provided a strong mathematical foundation to process systems engineering through the development of sophisticated mathematical and computational tools for the simulation, design, control, operation and optimization of chemical processes. In this article we first give a brief overview of his career that included several leadership positions and the establishment of the Centre for Process Systems Engineering (CPSE) at Imperial College London. We next review his research contributions in the areas of process modeling, differential algebraic systems, process dynamics and control, nonlinear optimization and optimal control, design under uncertainty, and process scheduling. We highlight the tremendous impact that he has had through his students, students' students, and his entire academic family tree, which at present contains over 2000 names, probably one of the largest among the academic leaders of chemical engineering. Finally, we provide a brief overview of him as a modest and charming individual with a wonderful sense of humor. He is without doubt a true intellectual giant who has helped to expand the scope of chemical engineering by providing a strong systems component to it, and by establishing strong multidisciplinary links with other fields. © 2016 American Institute of Chemical Engineers AIChE J, 62: 2951–2958, 2016     

The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin⁻CD11b⁻Ly6C^hi CD115⁺, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.     

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate‐based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC₅₀ value of 25.4 μm . Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low‐micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell‐permeable derivatives clearly showed a demethylase‐inhibition‐dependent antiproliferative effect against HL‐60 human promyelocytic leukemia cells.     

N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

The nuclear retinoic acid receptor‐related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (T_H17) cell proliferation. As such, synthetic small‐molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing T_H17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N‐arylsulfonyl indolines as RORγ agonists. Structure–activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX‐MS) analysis of RORγ–ligand complexes help rationalize the observed results.     

High porosity,responsive hydrogel copolymers from emulsion templating

Hydrogels, three‐dimensional hydrophilic polymer network structures, can absorb many times their dry weight in water. PolyHIPEs are highly porous polymers synthesized within high internal phase emulsions (HIPEs). Here, the water uptakes in novel hydrogel polyHIPE copolymers of hydroxyethyl methacrylate (HEMA, a non‐ionic monomer) and methacrylic acid (MAA, an ionic monomer) were investigated. The PHEMA‐based polyHIPE had a density of 0.14 g cm^?3, void diameters of 50–100 µm and a void‐dominated Fickian water uptake of around 10.4 g g^?1. The polyHIPE density increased, and the porous structure became less polyHIPE‐like, with increasing MAA content, reflecting a reduction in the stability of the HIPE. The water uptake increased with increasing pH for all the copolymers and the water absorption mechanism changed from Fickian at pH 2 to anomalous, dominantly case II, at pH 10. The maximum uptake of 18.2 g g^?1 at pH 10, for a HEMA to MAA mass ratio of 1/1, was ascribed to hydrogel‐swelling‐driven void expansion. The hydrogel's absorptive and responsive properties were amplified by the polyHIPE's porous structure. These results demonstrate that the compositions of hydrogel polyHIPE copolymers can be designed to enhance their water uptake. © 2015 Society of Chemical Industry     

Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice

The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1^−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1^−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1^−/− and wild type mice. GC1^−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1^−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1^−/− mice.     

Properties of phyllosilicate-based porous ceramics shaped by conventional tape casting and freeze tape casting

Silicate ceramics were shaped using tape casting (TC) and freeze tape casting (FTC) processes from three clays labeled HCR, KORS, and KCR. These clays exhibited mass content of 77% halloysite–10 Å, 29% kaolinite, and 98% kaolinite minerals, respectively. After casting the slurries, the dried tapes were sintered at 1200°C. The microstructure changes were characterized before and after sintering using scanning electron microscopy. The apparent porosity of TC samples was lower (36–47 vol.%) compared to values obtained with FTC samples (67–79 vol.%). The latter samples exhibited a highly textured porosity, with micron-sized pores aligned perpendicular to the tape surfaces. Upon sintering, the porosity of TC samples tended to decrease conversely to the case of FTC samples. Such behavior seemed related to the simultaneous effect of organic additives and ice templating. Consequently, the FTC samples showed a relatively low mechanical strength of 3–7 MPa and thermal conductivity of .14– .22 W m⁻¹ K⁻¹. After sintering, the mullite crystallization contributed to strengthen the bulk materials, helping to compensate for the detrimental effect of porosity on the stress to rupture and on thermal conductivity values.     

Aluminum to germanium inversion in mullite-type RAlGeO5: Characterization of a rare phenomenon for R = Y,Sm–Lu

Mullite-type RMn₂O₅ (R = Y, rare-earth element) ceramics are of ongoing research attentions because of their interesting crystal-chemical, physical, and thermal properties. We report a detailed structural, spectroscopic and thermal analysis of the series of mullite-type RAlGeO₅ (R = Y, Sm-Lu) phases. Polycrystalline samples are prepared by solid-state synthesis methods. Each sample is characterized by X-ray powder diffraction followed by Rietveld refinements, showing that they are isotypic and crystallize in the space group Pbam. The change of the metric parameters is explained in term of the lanthanide contraction effect. A rare inversion of Al/Ge between octahedral and pyramidal sites have been observed for these mullite-type so called O10 compounds, and the inversion parameter found to be between 0.22(1) and 0.30(1) for different R-cations. The <Al/Ge–O> bond distances and their bond valence sums (BVSs) support the respective inversions. Density functional theory (DFT) calculated phonon density of states (PDOS) and electronic band structures are compared for the vibrational and electronic band gap features respectively. Analysis of UV/Vis absorption spectra using both derivation of absorption spectra fitting (DASF) and Tauc's methods demonstrates that each of the RAlGeO₅ O10 compounds is high bandgap semiconductor, possessing direct transition between 4.1(1) and 5.4(1) eV. Both Raman and Fourier transform infrared spectra show clear red shift (quasi-harmonic) of the vibrational wavenumbers with respect to the ionic radii of the R-cations. Selective Raman bands at higher wavenumber region further complement the inversion of Al/Ge between two coordination sites. The higher decomposition temperature of the RAlGeO₅ compounds, compared to those of RMn₂O₅ phases, is explained in terms of higher bond strength of Al/Ge-O than those of Mn-O. Irrespective to the inversion between Al- and Ge-sites, the decomposition temperature also depends on the type of R-cation in RAlGeO₅.