Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives

Background: Many polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes. Results: The scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-3-ols is discussed. In the absence of a 6- substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water) and Donohoe (OsO4, TMEDA, CH2Cl2) conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R*) diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2'S)-6- methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)-1-(toluene-4-sulfonyl)-1,6- dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, twodirectional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues. Conclusion: A two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived from a sugar, allowing mimetics with unusual configurations to be prepared. The work demonstrates that highly unsymmetrical molecules may be prepared using a two directional approach. The deprotected compounds may have potential as inhibitors of oligosaccharide-processing enzymes and as tools in chemical genetic investigations

Influence of Post-AI Nutrition on Blood Urea Nitrogen, Progesterone, and Pregnancy

Research has shown that changes in nutrition can have an effect on reproductive performance. Our objective was to determine the effect of post-AI nutrition on BCS, blood urea nitrogen (BUN), progesterone, and pregnancy rates. Forage-developed Angus-cross bred heifers (n = 336) were synchronized with the Select Synch+ Controlled Internal Drug Releasing device (CIDR) protocol (d -7 100 μg GnRH and CIDR; d 0 25 mg PG and removal of CIDR). Estrus was detected for 72 h and heifers bred by AI 12 h after being detected in estrus; heifers not in detected in estrus were bred by AI and given an injection of GnRH at 72 h. Each breeding period was equally divided into three treatments: 1) heifers returned to feedlot (LOT), 2) heifers were moved to pasture (PASTURE), or 3) heifers were moved to pasture and supplemented with 5 lb/hd/d of dried distillers grains plus solubles (SUPP). Blood samples were collected on d -7, 0, 2, 14 and 42 (pregnancy determination; d 0 = AI). Body condition scores were determined on d -7 and 42. All heifers were in similar BCS (5.4 ± 0.05) on d -7, but on d 42 SUPP (5.9 ± 0.04) were in better condition than LOT (5.8 ± 0.04) which were in better condition than PASTURE (5.4 ± 0.04). All treatments had similar BUN concentrations on d -7 (129 ± 1), but on d 2, 14, and 42 SUPP had greater BUN concentrations compared to both LOT and PASTURE. There was no difference in BUN concentrations between pregnant and open heifers. Progesterone concentrations were similar among all heifers on d 0 and 2. On d 14, SUPP had greater progesterone concentrations compared to LOT, and on d 14 and 42 PASTURE had greater progesterone concentrations compared to LOT. Progesterone was similar for open and pregnant heifers on d 0 and 2, but greater in pregnant heifers on d 14 and 42. There was no difference among treatments in pregnancy rates (57, 56, and 59% for SUPP, LOT, and PASTURE; analyzed by chi-square). In summary, supplementing forage-developed heifers after insemination increased BCS and BUN concentrations but had no effect on pregnancy rates

Categorisation and Detection of Dark Matter Candidates from String/M-theory Hidden Sectors

We study well-motivated dark matter candidates arising from weakly-coupled hidden sectors in compactified string/$M$-theory. Imposing generic top-down constraints greatly restricts allowed candidates. By considering the possible mechanisms for achieving the correct dark matter relic density, we compile categories of viable dark matter candidates and annihilation mediators. We consider the case where supersymmetry breaking occurs via moduli stabilisation and is gravitationally mediated to the visible and other hidden sectors, without assuming sequestering of the sector in which supersymmetry is broken. We find that in this case, weakly-coupled hidden sectors only allow for fermionic dark matter. Additionally, most of the mechanisms for obtaining the full relic density only allow for a gauge boson mediator, such as a dark $Z'$. Given these considerations, we study the potential for discovering or constraining the allowed parameter space given current and future direct detection experiments, and direct production at the LHC. We also present a model of a hidden sector which would contain a satisfactory dark matter candidate.Comment: 29 pages, 10 figure

A comparison of structured and unstructured navigation through a CBT package

The advent of hypertext has opened up new possibilities in computer-based training. The design of courseware without any predetermined structure could make the designer's task easier, and allow greater flexibility for the trainee to structure the learning environment to suit their own learning style, This investigation was concerned with the exploration of performance differences in structured and unstructured training environments. In the structured condition, subjects encountered presequenced training and practice modules. For the unstructured condition, subjects determined their own sequence of modules. It was proposed that performance may be better in the unstructured condition. The findings indicate that this depends upon individual differences in cognitive style, some styles seemingly better at exploiting the unstructured learning environment than others

Genome-wide association study identifies common and low-frequency variants at the AMHgene locus that strongly predict serum AMH levels in males

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 M ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men

Introducing offlineness: theorizing (digital) literacy engagements

In this Insights essay, we propose a new concept of offlineness that builds on current language around digital practices, yet addresses an element of young people’s experience that is not adequately represented in current research or educational discourse. This work is informed by a recent cross-national arts-based research project that highlighted the limitations of the discourse ascribed to the nature of young people’s engagement with digital literacies. We propose a (re)theorization, which builds on a critical review of current conceptual research and digital commentaries. Theorizing offlineness as a continuum between online and offline practices is tantamount to a paradigm shift toward more nuanced understandings of young people’s digital practices. It offers researchers and educators a more precise way to speak to young people’s digital experiences, providing a productive tool to (re)construct learning and inquiry spaces in literacy research and education

Preterm gut microbiota and metabolome following discharge from intensive care

The development of the preterm gut microbiome is important for immediate and longer-term health following birth. We aimed to determine if modifications to the preterm gut on the neonatal intensive care unit (NICU) impacted the gut microbiota and metabolome long-term. Stool samples were collected from 29 infants ages 1–3 years post discharge (PD) from a single NICU. Additional NICU samples were included from 14/29 infants. Being diagnosed with disease or receiving increased antibiotics while on the NICU did not significantly impact the microbiome PD. Significant decreases in common NICU organisms including K. oxytoca and E. faecalis and increases in common adult organisms including Akkermansia sp., Blautia sp., and Bacteroides sp. and significantly different Shannon diversity was shown between NICU and PD samples. The metabolome increased in complexity, but while PD samples had unique bacterial profiles we observed comparable metabolomic profiles. The preterm gut microbiome is able to develop complexity comparable to healthy term infants despite limited environmental exposures, high levels of antibiotic administration, and of the presence of serious disease. Further work is needed to establish the direct effect of weaning as a key event in promoting future gut health

Assessment of Anwai river water quality using the weighted arithmetic water quality index (WQI) in Delta State, Nigeria

The weighted arithmetic water quality index method was used to assess the water quality of anthropogenically-laden Anwai-river within the Asaba-capital territory of Delta State, Nigeria, in Stations 1(Otulu), 2(Isele- asagba) and 3(Anwai-Asaba) using pH, electrical conductivity (EC), total dissolved solids (TDS), biochemical oxygen demand (BOD), dissolved oxygen (DO), turbidity, phosphates, nitrates, total hardness (TH) and coliforms, to determine its water quality status and its suitability for humans and aquatic biota. Aside from TDS, turbidity, and TH, other parameters such as pH (5.3-8.2), DO (2.0-2.8 mg/L), BOD (1.02-2.4 mg/L), EC (110-113 µS/cm), turbidity(2.3-5.2 NTU), TDS (8.0-16.0 mg/L), TH (30-62 mg/L), phosphates (0.13-0.28 mg/L), nitrates (0.05-0.27 mg/L) and Coliform (25.75-45.5 cfu/ml) indicated non-significant variableness (p>0.05) between Stations. Water depth, TDS, turbidity, TH, phosphate, nitrate and total coliform were significant contributors to the Anwai-river's water quality by Principal component analysis (PCA). The first principal component (PC1) exhibited 94.1% variance and a 0.1860 loading factor, while the second showed 5.9% variance and 0.0117 loading factor implying depth, flooding, excessive human activities and sewage disposal as important contaminants. Although the individual physiochemical-based water qualities were below the WHO recommended drinking water values translated into poor water quality by the weighted arithmetic water quality index at the three Stations; 86.83, 75.02 and 81.27 in Station's 1, 2 and 3 respectively, correspondingly poor to very poor based on Water quality index. The water of Anwai-river is a serious health threat to humans and aquatic organisms and thus, it should not be utilized untreated