PAT-based design of agrochemical co-crystallization processes : a case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamide/triphenylphosphine oxide

In this study, the selective crystallization and characterization of the stoichiometric forms of the p-toluenesulfonamide/triphenylphosphine oxide (p-TSA-TPPO) co-crystal system in acetonitrile (MeCN) is demonstrated using batch and semi-batch crystallizers. In the batch study, both 1:1 and 3:2 p-TSA-TPPO were successfully isolated as pure forms. However, process variability was observed in a few experimental runs. To address the batch process variability issue, a control strategy was implemented using temperature cycling, aided by in situ process analytical technologies (PAT) to convert from 3:2 to 1:1 p-TSA-TPPO. In the semi-batch co-crystallization studies, the two molecular co-formers, p-TSA and TPPO, were dissolved in MeCN and pumped separately to the crystallizer. Changing the flow rates of the respective active ingredients allowed control over the co-crystallization outcome, and presents as a promising opportunity for development of a continuous co-crystallization process

Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation

AbstractIn this paper, a novel concept of periodic mixed suspension mixed product removal (PMSMPR) crystallization process is demonstrated. An integrated array of process analytical technologies (PATs), based on attenuated total reflectance ultra violet/visible spectroscopy, focused beam reflectance measurement, particle vision microscopy and Raman spectroscopy, and in-house developed crystallization process informatics system software (CryPRINS) were used to monitor the periodic steady-state flow crystallization of paracetamol. Periodic steady-state is a new concept defined as a state of a system that maintains itself despite transitory effects caused by periodic, but controlled disruptions (state of controlled operation). This work also illustrates the concept of “state of controlled operation” instead of “steady-state operation” as a state that can characterize continuous (periodic) operation. The PMSMPR was configured as either a single- or two-stage unit and operated for up to 11 residence times without blockage or encrustation problems. The number of PMSMPR stages, seed characteristics (size, shape and distribution), and use of recycle stream were the main variables that influenced the periodic operation, significantly affecting the extent of secondary nucleation and growth. The results further illustrate the use of PAT and information system tools together to determine when the periodic operation reaches a state of controlled operation (periodic steady-state). These tools provided a better understanding of the variables and operating procedures influencing the periodic operation

A unique Valanginian paleoenvironment at an iron ore deposit near Zengővárkony (Mecsek Mts, South Hungary), and a possible genetic model

Abstract The spatially restricted Early Valanginian iron ore (limonite) and manganese deposit at Zengõvárkony (Mecsek Mts, southern Hungary) contains a rich, strongly limonitized, remarkably large-sized (specimens are 30–70% larger than those at their type localities) brachiopod-dominated (mainly Lacunosella and Nucleata) megafauna and a diverse crustacean microfauna, which indicates a shallow, nutrient-rich environment possibly linked to an uplifted block, and/or a hydrothermal vent

Population ecology of Psammobates oculifer in a semi-arid environment

We studied the ecology of Psammobates oculifer over 13 months near Kimberley, South Africa, to ascertain if the population’s life history traits conform to chelonian patterns in arid environments. Capture rates were highest in spring and lowest in winter when environmental conditions were respectively most and least favourable for tortoise activity. Body condition did not change from autumn to spring, but reached lower values during the summer drought. Capture effort averaged 5 hours/tortoise, which corresponds closely to that of species with low population densities in arid regions. Population size structure was skewed towards adults, indicative of low recruitment and/or low juvenile survivorship. Females were larger and heavier than males, confirming sexual dimorphism in this species. Body size of cohorts scaled to annuli counts, indicating a close correspondence between body size and age. Telemetered adults deposited one or no growth ring in the year of study; consequently, annuli counts could underestimate adult age. Regression analyses showed that male and female growth rates did not differ, but males matured at a smaller size and younger age than females. The smallest male showing reproductive behaviour had 12 annuli and a shell volume of 157 cm3, while similar measures for females were 14 annuli and 185 cm3. The sex ratio of the population did not differ from 1:1 but the bias towards males in spring, and towards females in autumn, indicates that studies limited to particular seasons can misrepresent life history traits of populations. We concluded that the life history of P. oculifer conforms to chelonian patterns in arid regions.Web of Scienc

Variation in the daily activity, movement and refugia of Critically Endangered geometric tortoises, Psammobates geometricus, in autumn and spring

To help assess habitat requirements of Critically Endangered geometric tortoises, we used thread-trailing to measure daily activity, movements and refugia of adult Psammobates geometricus in autumn and spring 2002. We found strong differences between seasons, and effects of weather, individuals and sex. The high activity was consistent with mild weather during autumn and spring. However, daily temperatures limited female movements on cool autumn days and male movements on warm spring days, a pattern consistent with sexual size dimorphism (large females and small males). The long movements in autumn probably helped tortoises find food plants that grow quickly after autumn rains; both sexes recover body condition from autumn lows, and females begin egg production in late-autumn and winter. These movements may also help males mate with females before they ovulate. The high activity of females in spring should help them forage and sustain their vitellogenesis, egg production and nesting in spring. Male paths tended to be more linear than female paths in both seasons, so this sexual difference is likely not linked to food consumption. Males may move long, linear paths to engage females and avoid other males. Males may have been thermally-challenged in spring. Their movements decreased with increased ground temperatures (in the sun), they used denser refugia in spring than in autumn, and in spring used denser refugia than females used. Geometric tortoises typically used different refugia on consecutive nights, a type of predator avoidance mechanism

Measurement of Bottom versus Charm as a Function of Transverse Momentum with Electron-Hadron Correlations in p+p Collisions at sqrt(s)=200 GeV

The momentum distribution of electrons from semi-leptonic decays of charm and bottom for mid-rapidity |y|<0.35 in p+p collisions at sqrt(s)=200 GeV is measured by the PHENIX experiment at the Relativistic Heavy Ion Collider (RHIC) over the transverse momentum range 2 < p_T < 7 GeV/c. The ratio of the yield of electrons from bottom to that from charm is presented. The ratio is determined using partial D/D^bar --> e^{+/-} K^{-/+} X (K unidentified) reconstruction. It is found that the yield of electrons from bottom becomes significant above 4 GeV/c in p_T. A fixed-order-plus-next-to-leading-log (FONLL) perturbative quantum chromodynamics (pQCD) calculation agrees with the data within the theoretical and experimental uncertainties. The extracted total bottom production cross section at this energy is \sigma_{b\b^bar}= 3.2 ^{+1.2}_{-1.1}(stat) ^{+1.4}_{-1.3}(syst) micro b.Comment: 432 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy

We review HB stars in a broad astrophysical context, including both variable and non-variable stars. A reassessment of the Oosterhoff dichotomy is presented, which provides unprecedented detail regarding its origin and systematics. We show that the Oosterhoff dichotomy and the distribution of globular clusters (GCs) in the HB morphology-metallicity plane both exclude, with high statistical significance, the possibility that the Galactic halo may have formed from the accretion of dwarf galaxies resembling present-day Milky Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the second-parameter problem is presented. A technique is proposed to estimate the HB types of extragalactic GCs on the basis of integrated far-UV photometry. The relationship between the absolute V magnitude of the HB at the RR Lyrae level and metallicity, as obtained on the basis of trigonometric parallax measurements for the star RR Lyrae, is also revisited, giving a distance modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are studied. Finally, the conductive opacities used in evolutionary calculations of low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and Space Scienc

HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus

Hyperpolarisation-activated (Ih) currents are considered important for dendritic integration, synaptic transmission, setting membrane potential and rhythmic action potential (AP) discharge in neurons of the central nervous system. Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels underlie these currents and are composed of homo- and hetero-tetramers of HCN channel subunits (HCN1–4), which confer distinct biophysical properties on the channel. Despite understanding the structure–function relationships of HCN channels with different subunit stoichiometry, our knowledge of their expression in defined neuronal populations remains limited. Recently, we have shownthat HCN subunit expression is a feature of a specific population of dorsal horn interneurons that exhibit high-frequency AP discharge. Here we expand on this observation and use neuroanatomical markers to first identify well-characterised neuronal populations in the lumbar spinal cord and hippocampus and subsequently determine whether HCN4 expression correlates with high-frequency AP discharge in these populations. In the spinal cord, HCN4 is expressed in several putative inhibitory interneuron populations including parvalbumin (PV)-expressing islet cells (84.1%; SD: ±2.87), in addition to all putative Renshaw cells and Ia inhibitory interneurons. Similarly, virtually all PVexpressing cells in the hippocampal CA1 subfield (93.5%;±3.40) and the dentate gyrus (90.9%; ±6.38) also express HCN4. This HCN4 expression profile in inhibitory interneurons mirrors both the prevalence of Ih sub-threshold currents and high-frequency AP discharge. Our findings indicate that HCN4 subunits are expressed in several populations of spinal and hippocampal interneurons, which are known to express both Ih sub-threshold currents and exhibit high-frequency AP discharge. As HCN channel function plays a critical role in pain perception, learning and memory,and sleep as well as the pathogenesis of several neurologicaldiseases, these findings provide important insights into the identity and neurochemical status of cells that could underlie such conditions

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Gaia Early Data Release 3: Gaia photometric science alerts

Context. Since July 2014, the Gaia mission has been engaged in a high-spatial-resolution, time-resolved, precise, accurate astrometric, and photometric survey of the entire sky. Aims. We present the Gaia Science Alerts project, which has been in operation since 1 June 2016. We describe the system which has been developed to enable the discovery and publication of transient photometric events as seen by Gaia. Methods. We outline the data handling, timings, and performances, and we describe the transient detection algorithms and filtering procedures needed to manage the high false alarm rate. We identify two classes of events: (1) sources which are new to Gaia and (2) Gaia sources which have undergone a significant brightening or fading. Validation of the Gaia transit astrometry and photometry was performed, followed by testing of the source environment to minimise contamination from Solar System objects, bright stars, and fainter near-neighbours. Results. We show that the Gaia Science Alerts project suffers from very low contamination, that is there are very few false-positives. We find that the external completeness for supernovae, CE = 0.46, is dominated by the Gaia scanning law and the requirement of detections from both fields-of-view. Where we have two or more scans the internal completeness is CI = 0.79 at 3 arcsec or larger from the centres of galaxies, but it drops closer in, especially within 1 arcsec. Conclusions. The per-Transit photometry for Gaia transients is precise to 1% at G = 13, and 3% at G = 19. The per-Transit astrometry is accurate to 55 mas when compared to Gaia DR2. The Gaia Science Alerts project is one of the most homogeneous and productive transient surveys in operation, and it is the only survey which covers the whole sky at high spatial resolution (subarcsecond), including the Galactic plane and bulge. © S. T. Hodgkin et al. 2021