Feeding graded levels of dried Sea buckthorn (Hippophaes rhamnoides) berries to broiler chickens

The aim of this study was to assess the effects of graded levels (0, 3, 6, 9 and 12 g/kg) of dry Sea buckthorn (SB) berries on growth performance, gastrointestinal tract (GIT) development, jejunal histomorphology, bird antioxidant status and caecal short-chain fatty acid concentration when fed to female Ross 308 broiler chickens. In addition, expression of cytokine biomarker genes in the jejunum was evaluated. The five experimental diets were fed from 7 to 21 days age to 8 pens (two birds in each) following randomisation. Feeding SB did not influence bird growth performance (p > .05). There was a linear decrease in butyric, acetic and valeric acid concentrations in caecal digesta (p < .05) and a decrease (p < .05) in crypt depth. The expression of IFNG and CD40LG responded quadratically (p < .05), peaking at 6–9 g/kg dietary inclusion of SB, respectively. Other studied variables were not affected by dietary SB inclusion (p > .05). Feeding dry SB berries up to 12 g/kg of diet did not improve the zootechnical variables of healthy commercial-strain broilers in this study.     

Properties of STAT1 and IRF1 enhancers and the influence of SNPs

Background

STAT1 and IRF1 collaborate to induce interferon-γ (IFNγ) stimulated genes (ISGs), but the extent to which they act alone or together is unclear. The effect of single nucleotide polymorphisms (SNPs) on in vivo binding is also largely unknown.

Results

We show that IRF1 binds at proximal or distant ISG sites twice as often as STAT1, increasing to sixfold at the MHC class I locus. STAT1 almost always bound with IRF1, while most IRF1 binding events were isolated. Dual binding sites at remote or proximal enhancers distinguished ISGs that were responsive to IFNγ versus cell-specific resistant ISGs, which showed fewer and mainly single binding events. Surprisingly, inducibility in one cell type predicted ISG-responsiveness in other cells. Several dbSNPs overlapped with STAT1 and IRF1 binding motifs, and we developed methodology to rapidly assess their effects. We show that in silico prediction of SNP effects accurately reflects altered binding both in vitro and in vivo.

Conclusions

These data reveal broad cooperation between STAT1 and IRF1, explain cell type specific differences in ISG-responsiveness, and identify genetic variants that may participate in the pathogenesis of immune disorders.

     

Sex‐related differences in the postmolt distribution of Weddell seals (Leptonychotes weddellii) in the southern Weddell Sea

The population of Weddell seals (Leptonychotes weddellii) in the southern Weddell Sea is in a unique position on the continental shelf edge, with vast shelf waters to the south, and deep Southern Ocean to the north. We describe sex‐related differences in the winter distribution of this population, from data collected by 20 conductivity‐temperature‐depth satellite relay data loggers deployed in February 2011 at the end of the annual molt. The regional daily speed was calculated, and a state‐space model was used to estimate behavioral states to positions along individuals’ tracks. GLMMs estimated that males and smaller individuals, diving in shallower water, traveled less far per day of deployment (males 14.6 ± 2.26 km/d, females 18.9 ± 2.42 km/d), and males were estimated to dive in shallower water (males 604 ± 382 m, females 1,875 ± 1,458 m). Males and smaller individuals were also estimated to be more resident; males spent an average 83.4% ± 7.7% of their time in a resident behavioral state, compared to females at 74.1% ± 7.1%. This evidence that male and female Weddell seals in the southern Weddell Sea are adopting different strategies has not been shown elsewhere along their circumpolar distribution.     

The prion-like domain of Fused in Sarcoma is phosphorylated by multiple kinases affecting liquid- and solid-phase transitions

Fused in Sarcoma (FUS) is a ubiquitously expressed protein that can phase-separate from nucleoplasm and cytoplasm into distinct liquid-droplet structures. It is predominantly nuclear and most of its functions are related to RNA and DNA metabolism. Excessive persistence of FUS within cytoplasmic phase-separated assemblies is implicated in the diseases amyotrophic lateral sclerosis and frontotemporal dementia. Phosphorylation of FUS’s prion-like domain (PrLD) by nuclear phosphatidylinositol 3-kinase-related kinase (PIKK)-family kinases following DNA damage was previously shown to alter FUS’s liquid-phase and solid-phase transitions in cell models and in vitro. However, proteomic data suggest that FUS’s PrLD is phosphorylated at numerous additional sites, and it is unknown if other non-PIKK and nonnuclear kinases might be influencing FUS’s phase transitions. Here we evaluate disease mutations and stress conditions that increase FUS accumulation into cytoplasmic phase-separated structures. We observed that cytoplasmic liquid-phase structures contain FUS phosphorylated at novel sites, which occurred independent of PIKK-family kinases. We engineered phosphomimetic substitutions within FUS’s PrLD and observed that mimicking a few phosphorylation sites strongly inhibited FUS solid-phase aggregation, while minimally altering liquid-phase condensation. These effects occurred independent of the exact location of the phosphomimetic substitutions, suggesting that modulation of PrLD phosphorylation may offer therapeutic strategies that are specific for solid-phase aggregation observed in disease.     

Long-term Chikungunya sequelae and quality of life 2.5 years post-acute disease in a prospective cohort in Curaçao

BackgroundLittle is known about the persistence and impact of non-rheumatic symptoms after acute chikungunya disease. We have studied the clinical presentation and long-term impact of rheumatic and non-rheumatic symptoms on health related quality of life (QoL) 2.5 years after disease onset. Additionally, the validity of the Curaçao Long-Term Chikungunya Sequelae (CLTCS) score in classifying disease severity over time was evaluated.Methodology/Principal findingsThis prospective cohort study followed 248 chikungunya patients. Symptoms and SF-36 QoL were evaluated during baseline and follow-up at 2.5 years using questionnaires. Chikungunya disease status was classified using the CLTCS-score. At 2.5 years after disease onset patients were classified as being recovered (43%), mildly (35%) or highly (22%) affected. In comparison to mildly affected, highly affected patients reported the highest prevalence of ongoing rheumatic and non-rheumatic/psychological symptoms, with increased prevalence of arthralgia in the lower extremities (p = .01) and fatigue (p = .049) over time, and higher pain intensity (p < .001). Compared to mildly affected, being highly affected was associated with weakness in the lower extremities (OR: 1.90; CI: 1.29–2.80, p = .001) and worsened physical and mental QoL impairment.ConclusionsPatients are both physically and psychologically affected by rheumatic and non-rheumatic symptoms of long-term chikungunya disease.The CLTCS-score is an easy to use instrument for classifying long-term chikungunya disease severity and impact and can facilitate health care providers in identifying highly affected patients who are prone to develop severe QoL impairment. Highly affected patients are recommended to be treated in a multidisciplinary setting to improve physical and psychological functioning, and QoL.     

The discovery and optimisation of benzazepine sulfonamide and sulfones as potent agonists of the motilin receptor

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.