Synthesis, structures and reactions of new cyclometallated dinuclear gold complexes containing the fluorine-substituted ligands

The dinuclear cyclometallated gold(I) complex [Au2(μ-2-C6F4PPh2)2] was prepared in high yield from the reaction of 2-LiC6F4PPh2 with either [AuBr(AsPh3)] or [AuCl(tht)], and from the reaction of 2-Me3SnC6F4PPh2 with [AuCl(tht)]. The digold(I) complex undergoes oxidative addition reactions with halogens to give the metal-metal bonded dihalodigold(II) complexes [Au2IIX2(μ-2-C6F4PPh2)2] (X = Cl, Br, I), which on warming or exposure to light, isomerise to give the heterovalent gold(I)-gold(III) species [XAu(µ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuX] containing a four-membered cyclometallated ring on a gold(III) centre. Unlike its protio analogue, [Au2(μ-2-C6F4PPh2)2] did not undergo oxidative addition of methyl iodide or dibenzoyl peroxide. The dihalodigold(II) [Au2IIX2(μ-2-C6F4PPh2)2] and gold(I)-gold(III) compounds [XAu(µ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuX] (X = Cl, Br) are further oxidised by halogens to give the digold(III) species [Au2X4(μ-2-C6F4PPh2)2] and [X3Au(μ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuX], respectively. The complexes [Au2X4(μ-2-C6F4PPh2)2] are reduced to the dihalodigold(II) complexes in the presence of one equivalent of zinc powder; further addition of zinc gave the parent digold(I) dimer. Treatment of [Au2IICl2(μ-2-C6F4PPh2)2] and [ClAu(µ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuCl] with an excess of silver nitrate, benzoate, acetate, trifluoroacetate or triflate gave the corresponding oxyanion complexes. Slow crystallisation of the di(benzoato)digold(II) complex from dichloromethane and methanol gave the parent digold(I) complex derived by reductive elimination. The di(triflato)digold(II) complex behaved similarly, although in this case the novel gold(I) tetramer [Au4(μ-2-C6F4PPh2)4] was formed together with the dimer. Two closely related gold complexes containing the chelating κ2(C,O) phosphine oxide ligand, 2-C6F4P(O)PPh2, were isolated from the reaction of [ClAu(µ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuCl] with an excess of silver nitrate. The reaction of [Au2IICl2(μ-2-C6F4PPh2)2] with two equivalents of potassium trifluoroethoxide failed to give the corresponding digold(II) bis(alkoxo) complex; instead, reduction took place to form the digold(I) dimer [Au2(μ-2-C6F4PPh2)2]. Treatment of a solution of the di(benzoato)digold(II) complex with C6F5Li gave the pentafluorophenyl complex [Au2(C6F5)2(μ-2-C6F4PPh2)2] which, when heated in toluene, rearranged to the gold(I)-gold(III) complex [(C6F5)Au(µ-2-C6F4PPh2)(κ2-2-C6F4PPh2)Au(C6F5)], analogous to the behaviour of the dihalodigold(II) complexes. The heterovalent, gold(I)-gold(III) dimethyl compound [Au2I,III(CH3)2(μ-2-C6F4PPh2)2] was obtained from the reaction of the di(benzoato)digold(II) complex with dimethylzinc. This compound is structurally similar to its tetraprotio analogue. The cycloaurated dinuclear gold complexes [Au2(μ-C6H3-n-F-2-PPh2)2] (n = 5, 6) were made similarly to the 2-C6F4PPh2 analogue from the appropriate lithium or tin reagents, though in some cases the dimers were formed in admixture with the corresponding gold(I) tetramers. Like their tetrafluoro analogues, the 6-fluoro complexes [Au2X2(μ-C6H3-6-F-2-PPh2)2] (X = Cl, Br, I) rearrange on heating to give the heterovalent gold(I)-gold(III) species [XAu(µ-C6H3-6-F-2-PPh2)(κ2-C6H3-6-F-2-PPh2)AuX]. Thus, the presence of a fluorine atom in place of hydrogen in the 6-position of the bridging aryl group is sufficient to stop the isomerisation of the digold(II) complexes [Au2X2(μ-2-C6H4PPh2)2] at the gold(I)-gold(III) stage and to prevent subsequent C-C coupling of the aryl groups at the gold(III) centre. In contrast, the dihalodigold(II) complexes containing the 5-fluoro substituted ligand undergo reductive elimination and coupling of the metallated aryl groups to give the digold(I) biphenyldiyl complexes [Au2X2(2,2'-Ph2P-5-FC6H3C6H3-5-F-PPh2)] (X = Cl, Br, I). The described complexes were characterised using 1H NMR, 31P NMR, 19F NMR spectroscopy, elemental analysis, mass spectroscopy, IR spectroscopy, X-ray diffraction and 197Au Mössbauer spectroscopy

On the Use of Hydrodynamic Instability Test as an Efficient Tool for Evaluating Viscoelastic Fluid Models

Abstract The so-called ''second-order'' rheological model has been of widespread use in studies related to viscoelastic fluids. The model, however, has been shown by Mathematics Subject Classification: 76E2

The Mondrian Data Engine

The increasing demand for extracting value out of ever-growing data poses an ongoing challenge to system designers, a task only made trickier by the end of Dennard scaling. As the performance density of traditional CPU-centric architectures stagnates, advancing compute capabilities necessitates novel architectural approaches. Near-memory processing (NMP) architectures are reemerging as promising candidates to improve computing efficiency through tight coupling of logic and memory. NMP architectures are especially fitting for data analytics, as they provide immense bandwidth to memory-resident data and dramatically reduce data movement, the main source of energy consumption. Modern data analytics operators are optimized for CPU execution and hence rely on large caches and employ random memory accesses. In the context of NMP, such random accesses result in wasteful DRAM row buffer activations that account for a significant fraction of the total memory access energy. In addition, utilizing NMP’s ample bandwidth with fine-grained random accesses requires complex hardware that cannot be accommodated under NMP’s tight area and power constraints. Our thesis is that efficient NMP calls for an algorithm-hardware co-design that favors algorithms with sequential accesses to enable simple hardware that accesses memory in streams. We introduce an instance of such a co-designed NMP architecture for data analytics, the Mondrian Data Engine. Compared to a CPU-centric and a baseline NMP system, the Mondrian Data Engine improves the performance of basic data analytics operators by up to 49× and 5×, and efficiency by up to 28× and 5×, respectively

Topographical analysis of the subependymal zone neurogenic niche

The emerging model for the adult subependymal zone (SEZ) cell population indicates that neuronal diversity is not generated from a uniform pool of stem cells but rather from diverse and spatially confined stem cell populations. Hence, when analysing SEZ proliferation, the topography along the anterior-posterior and dorsal-ventral axes must be taken into account. However, to date, no studies have assessed SEZ proliferation according to topographical specificities and, additionally, SEZ studies in animal models of neurological/psychiatric disorders often fail to clearly specify the SEZ coordinates. This may render difficult the comparison between studies and yield contradictory results. More so, by focusing in a single spatial dimension of the SEZ, relevant findings might pass unnoticed. In this study we characterized the neural stem cell/progenitor population and its proliferation rates throughout the rat SEZ anterior-posterior and dorsal-ventral axes. We found that SEZ proliferation decreases along the anterior-posterior axis and that proliferative rates vary considerably according to the position in the dorsal-ventral axis. These were associated with relevant gradients in the neuroblasts and in the neural stem cell populations throughout the dorsal-ventral axis. In addition, we observed spatially dependent differences in BrdU/Ki67 ratios that suggest a high variability in the proliferation rate and cell cycle length throughout the SEZ; in accordance, estimation of the cell cycle length of the neuroblasts revealed shorter cell cycles at the dorsolateral SEZ. These findings highlight the need to establish standardized procedures of SEZ analysis. Herein we propose an anatomical division of the SEZ that should be considered in future studies addressing proliferation in this neural stem cell niche.Fundação para a Ciência e a Tecnologia (FCT

An EBSD study of the deformation of service-aged 316 austenitic steel

Electron backscatter diffraction (EBSD) has been used to examine the plastic deformation of an ex-service 316 austenitic stainless steel at 297K and 823K (24 °C and 550 °C)at strain rates 3.5x10-3 to 4 x 10-7 s-1. The distribution of local misorientations was found to depend on the imposed plastic strain following a lognormal distribution at true strains 0.1. At 823 K (550 °C), the distribution of misorientations depended on the applied strain rate. The evolution of lattice misorientations with increasing plastic strain up to 0.23 was quantified using the metrics kernel average misorientation, average intragrain misorientation, and low angle misorientation fraction. For strain rate down to 10-5 s-1 all metrics were insensitive to deformation temperature, mode (tension vs. compression) and orientation of the measurement plane. The strain sensitivity of the different metrics was found to depend on the misorientation ranges considered in their calculation. A simple new metric, proportion of undeformed grains, is proposed for assessing strain in both aged and unaged material. Lattice misorientations build up with strain faster in aged steel than in un-aged material and most of the metrics were sensitive to the effects of thermal aging. Ignoring aging effects leads to significant overestimation of the strains around welds. The EBSD results were compared with nanohardness measurements and good agreement established between the two techniques of assessing plastic strain in aged 316 steel

The Probable Cell of Origin of NF1- and PDGF-Driven Glioblastomas

Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system

LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals