Ashbyjenkins8114

Polysorbates (PS) are surfactants commonly added in a therapeutic protein drug product as excipients to protect proteins from denaturation and aggregation during storage, transportation, and delivery. Significant degradation of PS in drug products could lead to shortened drug shelf lives and PS-degrading activity in drug products must be minimized. Identification of lipases that degrade PS could lead to better process control in drug manufacturing. In 2016, phospholipase B-like 2 (PLBD2) was proposed as a residual host cell protein responsible for degrading PS20 in a drug formulation. We have carried out a series of studies to verify the role of PLBD2 in degrading polysorbates in drug products purified from recombinant Chinese Hamster Ovary (CHO) cells. Genetic knock-out and immuno-depletion results showed that when PLBD2 was removed or depleted, the degradation of PS20 or PS80 was neither diminished nor reduced. In addition, a quantitative analysis of PLBD2 and PS20 degradation in multiple formulated mAb products did not establish a correlation between the amount of PLBD2 and the level of PS20 degradation. Collectively these results suggest that PLBD2 is not the primary cause of polysorbate degradation in formulated drug products purified using standard Protein A and ion exchange chromatography.Asparagine (Asn) deamidation is a common posttranslational modification in which Asn is converted to aspartic acid or isoaspartic acid. By introducing a negative charge, deamidation could potentially impact the binding interface and biological activities of protein therapeutics. We identified a deamidation variant in moxetumomab pasudotox, an immunotoxin Fv fusion protein drug derived from a 38-kDa truncated Pseudomonas exotoxin A (PE38) for the treatment of hairy-cell leukemia. Although the deamidation site, Asn-358, was outside of the binding interface, the modification had a significant impact on the biological activity of moxetumomab pasudotox. Surprisingly, the variant eluted earlier than its unmodified form on anion exchange chromatography, which often leads to the conclusion that it has a higher positive charge. Here we describe the characterization of the deamidation variant with differential scanning calorimetry and hydrogen-deuterium exchange mass spectrometry, which revealed that the Asn-358 deamidation caused the conformational changes in the catalytic domain of the PE38 region. These results provide an explanation for why the deamidation affected the biological activity of moxetumomab pasudotox and suggest the approach that can be used for process control to ensure product quality and process consistency.Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of Ac4MAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of Ac4MAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (As2O3, ATO)-loaded lipncer.Duck Tembusu virus (DTMUV), an emerging infectious pathogen, has caused severe disease in ducks and huge economic losses to the poultry industry in China since 2009. Despite considerable advances in understanding the effects of microRNAs on host antiviral immune responses, it remains unclear how miRNAs regulate DTMUV replication in duck embryo fibroblast (DEF) cells. This study aims to clarify the role of host microRNA-148a-5p (miR-148a-5p) in regulating DTMUV replication by targeting SOCS1. First, we found that during DTMUV infection, the expression of miR-148a-5p in DEFs was downregulated in a time-dependent and dose-dependent manner, while the expression of SOCS1 was significantly upregulated. In addition, we found that when miR-148a-5p mimics were transfected into DEFs, viral RNA copies, viral E protein expression levels and viral titres, which represent viral replication and proliferation, were significantly downregulated, while the opposite result was observed when miR-148a-5p inhibitor was transfected .It is unclear what non-pharmacological interventions to prevent cognitive decline should comprise. We systematically reviewed lifestyle and psychosocial interventions that aimed to reduce cognitive decline in healthy people aged 50+, and people of any age with Subjective Cognitive Decline or Mild Cognitive Impairment. We narratively synthesised evidence, prioritising results from studies rated as at lower Risk of Bias (ROB) and assigning Centre for Evidence Based Medicine grades. We included 64 papers, describing psychosocial (n = 12), multi-domain (n = 10), exercise (n = 36), and dietary (n = 6) interventions. We found Grade A evidence that over 4+ months aerobic exercise twice weekly had a moderate effect on global cognition in people with/ without MCI; and interventions that integrate cognitive and motor challenges (e.g. dance, dumb bell training) had small to moderate effects on memory or global cognition in people with MCI. We found Grade B evidence that 4+ months of creative art or story-telling groups in people with MCI; 6 months of resistance training in people with MCI and a two-year, dietary, exercise, cognitive training and social intervention in people with or without MCI had small, positive effects on global cognition. Effects for some intervention remained up to a year beyond facilitated sessions.Amyloid β-peptides (Aβ) are considered as a major hallmark of Alzheimer's disease (AD) that can induce synaptic loss and apoptosis in brain regions, particularly in the cortex and the hippocampus. Evidence suggests that crocin, as the major component of saffron, can exhibit neuromodulatory effects in AD. However, specific data related to their efficacy to attenuate the synaptic loss and neuronal death in animal models of AD are limited. Olaparib Hence, we investigated the efficacy of crocin in the CA3 and dentate gyrus (DG) regions of the hippocampus and also in frontal cortex neurons employing a rat model of AD. Male Wistar rats were randomly divided into control, sham, AD model, crocin, and AD model + crocin groups, with 8 rats per group. AD model was established by injecting Aβ1-42 into the frontal cortex rats, and thereafter the rats were administrated by crocin (30 mg/kg) for a duration of 12-day. The number of live cells, neuronal arborization and apoptosis were measured using a Cresyl violet, Golgi-Cox and TUNEL staining, respectively.