Dialysable leucocyte transfer factor in monkey and man

After review of the literature, this thesis describes the extent of cellular responses to selective antigens in vivo, and to antigens and phytohaemagglutinin in vitro in immunised and transfer factor-treated rhesus monkeys. Preliminary in vitro and fractionation studies of rhesus and human transfer factor preparations are also presented. In immunised animals an antigen-specific active sensitisation was detected by the skin delayed hypersensitivity (DH), the mixed leucocyte-macrophage migration (LMMI) and the lymphocyte transformation (LT) tests. In animals treated with rhesus dialysable transfer factor, adoptive transfer of sensitisation, with a specificity related to antigen- sensitivity of the donor(s) (i.e. "Donor-specific") was detected only by the LMMI-test. The relationship between the various tests was determined. In immunised monkeys, the antigen-stimulated LMMI- and LT-reactivities associated with each other and with the DH-reactivity. In contrast, in transfer factor-treated animals, these reactivities were apparently dissociated. Thus, in transfer factor recipients, dissociation either- reflected different sensitivity of the tests or indicated preferential lymphokine production. Phytohaemagglutinin-stimulated transformation was depressed in immunised animals, whilst 1t was elevated in transfer factor-treated monkeys probably indicating an "adjuvant-like" activity. Thus the results suggest that transfer factor had specific and non-specific in vivo activities 1n the rhesus monkey model. The in vitro study of human or rhesus monkey dialysable transfer factor in antigen-stimulated transformation tests showed augmenting and suppressive effects with antigen-immune or non-1mmune transfer factor. The degree of augmentation was related to the degree of antigen-sensitivity of the "recipient" (1.e. "Recipient-specific"). Thus, the in vitro activity of rhesus monkey or human transfer factor was non-specific. Preliminary Sephadex G-25 chromatography of human and rhesus monkey dialysable transfer factor preparations revealed 9-11 fractionable peaks with different absorption ratios, suggesting heterogeneity of composition

Evidence for Human Fronto-Central Gamma Activity during Long-Term Memory Encoding of Word Sequences

Although human gamma activity (30–80 Hz) associated with visual processing is often reported, it is not clear to what extend gamma activity can be reliably detected non-invasively from frontal areas during complex cognitive tasks such as long term memory (LTM) formation. We conducted a memory experiment composed of 35 blocks each having three parts: LTM encoding, working memory (WM) maintenance and LTM retrieval. In the LTM encoding and WM maintenance parts, participants had to respectively encode or maintain the order of three sequentially presented words. During LTM retrieval subjects had to reproduce these sequences. Using magnetoencephalography (MEG) we identified significant differences in the gamma and beta activity. Robust gamma activity (55–65 Hz) in left BA6 (supplementary motor area (SMA)/pre-SMA) was stronger during LTM rehearsal than during WM maintenance. The gamma activity was sustained throughout the 3.4 s rehearsal period during which a fixation cross was presented. Importantly, the difference in gamma band activity correlated with memory performance over subjects. Further we observed a weak gamma power difference in left BA6 during the first half of the LTM rehearsal interval larger for successfully than unsuccessfully reproduced word triplets. In the beta band, we found a power decrease in left anterior regions during LTM rehearsal compared to WM maintenance. Also this suppression of beta power correlated with memory performance over subjects. Our findings show that an extended network of brain areas, characterized by oscillatory activity in different frequency bands, supports the encoding of word sequences in LTM. Gamma band activity in BA6 possibly reflects memory processes associated with language and timing, and suppression of beta activity at left frontal sensors is likely to reflect the release of inhibition directly associated with the engagement of language functions

A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.

Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients

Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): From pharmacological inhibition in vitro to targeted siRNA therapy in vivo

Connective tissue growth factor (CCN2) is a major pro-fibrotic factor that frequently acts downstream of transforming growth factor beta (TGF-β)-mediated fibrogenic pathways. Much of our knowledge of CCN2 in fibrosis has come from studies in which its production or activity have been experimentally attenuated. These studies, performed both in vitro and in animal models, have demonstrated the utility of pharmacological inhibitors (e.g. tumor necrosis factor alpha (TNF-α), prostaglandins, peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, statins, kinase inhibitors), neutralizing antibodies, antisense oligonucleotides, or small interfering RNA (siRNA) to probe the role of CCN2 in fibrogenic pathways. These investigations have allowed the mechanisms regulating CCN2 production to be more clearly defined, have shown that CCN2 is a rational anti-fibrotic target, and have established a framework for developing effective modalities of therapeutic intervention in vivo

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Investigating the Efficiency of Biological Filters for Ammonia Removal

  Backgrounds and Aims: Ammonia removal from air to prevent severe damage to the environment and living organisms is very important. Biofiltration is an efficient, easy, cost-effective, and environmentally friendly process for degradation of ammonia from waste air. The aim of this study is to investigate the efficiency of biological filtration using a compost and scallop bed for ammonia removal. Materials and Methods: According to the ammonia removal method a column with 14cm inner diameter and 45cm height made from transparent Plexiglas was used. The column was filled up to 25 cm with compost and scallop (with a scallop: compost ratio of 1:4).  In this study, performance of the biofilter was studied under 10 different flow rates (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 lit/min) and 5 different concentrations (0-20, 20-40, 40-60, 60-80 and 80-100 ppm) at a temperature of 25 degrees Celsius. Results: The results of this study showed that efficiency is decreased when the flow rate or concentration is increased because the microbial population is reduced. The efficiency was reduced by 84.6-98.2 percent. Maximum efficiency occurred at a 0.19g/(m3.h) loading rate. Efficiency was in 0-20 concentration intervals at a flow rate of 1 lit/min and at an Empty Bed Residence Time (EBRT) of 240 seconds. Conclusion: The results show that a biofilter with a compost and scallop bed is efficient for ammonia removal from air. 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