Therapeutic monoclonal antibodies and their derivatives are key components of clinical pipelines in the global biopharmaceutical industry. The availability of large datasets of antibody sequences, ...structures, and biophysical properties is increasingly enabling the development of predictive models and computational tools for the "developability assessment" of antibody drug candidates. Here, we provide an overview of the antibody informatics tools applicable to the prediction of developability issues such as stability, aggregation, immunogenicity, and chemical degradation. We further evaluate the opportunities and challenges of using biopharmaceutical informatics for drug discovery and optimization. Finally, we discuss the potential of developability guidelines based on in silico metrics that can be used for the assessment of antibody stability and manufacturability.
The aim of this study was to determine if changes in omega-3 polyunsaturated fatty acid status following tuna oil supplementation correlated with changes in scores of depression. A total of 95 ...volunteers receiving treatment for major depression were randomised to consume 8 × 1 g capsules per day of HiDHA (2 g DHA, 0.6 g EPA and 10 mg Vitamin E) or olive oil (placebo) for 16 weeks, whilst undergoing weekly counseling sessions by trained clinical psychologists using a standard empirically validated psychotherapy. Depression status was assessed using the 17 item Hamilton rating scale for depression and the Beck Depression Inventory by a psychodiagnostician who was blind to the treatment. Blood was taken at baseline and 16 weeks (
n
= 48) for measurement of erythrocyte fatty acids. With HiDHA supplementation, erythrocyte DHA content rose from 4.1 ± 0.2 to 7.9 ± 0.4 % (mean ± SEM,
p
< 0.001) of total fatty acids but did not change (4.0 ± 0.2 to 4.1 ± 0.2 %) in the olive oil group. The mean changes in scores of depression did not differ significantly between the two groups (−12.2 ± 2.1 for tuna oil and −14.4 ± 2.3 for olive oil). However, analysis of covariance showed that in the fish oil group there was a significant correlation (
r
= −0.51) between the change in erythrocyte DHA and the change in scores of depression (
p
< 0.05). Further study of the relationship between DHA and depression is warranted.
Dietary deficiencies in essential omega-3 polyunsaturated fatty acids derived from fish are associated with depression and some fish oils may have therapeutic benefits. We aimed to determine whether ...taking tuna fish oil confers any additional benefit to conventional outpatient treatment for major depression. A randomized double-blind placebo-controlled four-month trial comparing tuna fish oil versus placebo was conducted on 83 outpatients with major depression. Despite large reductions in depression there were no significant differences at any assessment time point between patients receiving fish oil compared to placebo. Red blood cell incorporation of fatty acids indicated good compliance with oil supplementation, although this sample was not initially deficient in omega-3s. This particular dose and type of fish oil conferred no additional benefit to conventional treatment of depression in this sample. Future studies could target participants with pre-existing omega-3 deficiency and appraise alternate enriched types and higher doses of omega-3 supplementation.
Abstract
Arrays of 3D position-sensitive detectors (3DPSD), operating at room temperature and using cadmium zinc telluride (CZT) and thallium bromide (TIBr) sensors, are suitable for gamma-ray ...spectrometry in many applications. One detector configuration, the 3D position-sensitive Virtual Frisch-Grid detector (VFG), is particularly advantageous for integrating into large area arrays. The signals generated inside each detector of the array are captured with the anode, cathode and four pads that enable the reconstruction of the position and energy of the ionizing interaction by measurements of amplitude and timing of the signals. For these applications, a low-noise front-end ASIC has been developed, capable of processing bipolar signals (needed because of AC-coupling of certain electrodes). The ASIC can be coupled to an ADC in order to form a compound “waveform digitizer” capable of post-processing the analog signals and determining amplitude and timing information. This paper describes a 32-channel front-end ASIC that is suitable for reading out a 3 × 3 or 4 × 4 element matrix in the VFG configuration. Each channel is composed of a low-noise charge amplifier with an adaptive continuous reset feedback circuit suitable for both positive and negative charge, a first order shaper and a single-to-differential converter output stage. Voltage and current references are all internally generated by 10-bit DACs and the chip is fully controllable with the I
2
C communication protocol. The readout channel response has been verified using the implemented injection circuit. Linear behavior up to ∼75 ke
±
with the gain of ∼80 mV/fC, and up to ∼200 ke
±
with the gain of ∼30 mV/fC was demonstrated. In conclusion, the first test result waveforms using a
137
Cs radioactive source on a 5 × 5 × 12 mm
3
TIBr crystal are reported.
John R. Deane Jr. (1919--2013) was born with all the advantages a man needs to succeed in a career in the US Army, and he capitalized on his many opportunities in spectacular fashion. The son of one ...of George C. Marshall's closest assistants, Deane graduated from West Point with the first class of World War II and served in combat under the dynamic General Terry de la Mesa Allen Sr. After the war, he led a German espionage unit in operations against the Soviets, personally led the first foot patrol following the course of the Berlin Wall as it was being constructed, participated in the 1965 Dominican Republic intervention, and saw combat in Vietnam. In 1975, he received his fourth star and became commander of the US Army Materiel Development and Readiness Command.
InLessons in Leadership, this exceptional soldier not only discusses working with some of the army's most influential and colorful leaders -- including James M. Gavin, William E. DePuy, William Westmoreland, and Creighton Abrams Jr. -- but also the many junior officers who helped him develop the leadership skills for which he became well known. Throughout, he offers eyewitness accounts of key Cold War--era events as well as wise observations concerning the leadership and management challenges facing the Department of Defense. Ably edited and annotated by Jack C. Mason, Deane's illuminating memoir also features interviews with several of Deane's contemporaries, whose comments and recollections are interspersed to provide depth and context to the narrative.
The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation and cancer. While coding variation in HLA genes has been ...extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.
Adverse childhood experiences (ACEs) of parents are associated with a variety of negative health outcomes in offspring. Little is known about the mechanisms by which ACEs are transmitted to the next ...generation. Given that maternal depression and anxiety are related to ACEs and negatively affect children's behaviour, these exposures may be pathways between maternal ACEs and child psychopathology. Child sex may modify these associations. Our objectives were to determine: (1) the association between ACEs and children's behaviour, (2) whether maternal symptoms of prenatal and postnatal depression and anxiety mediate the relationship between maternal ACEs and children's behaviour, and (3) whether these relationships are moderated by child sex. Pearson correlations and latent path analyses were undertaken using data from 907 children and their mothers enrolled the Alberta Pregnancy Outcomes and Nutrition study. Overall, maternal ACEs were associated with symptoms of anxiety and depression during the perinatal period, and externalizing problems in children. Furthermore, we observed indirect associations between maternal ACEs and children's internalizing and externalizing problems via maternal anxiety and depression. Sex differences were observed, with boys demonstrating greater vulnerability to the indirect effects of maternal ACEs via both anxiety and depression. Findings suggest that maternal mental health may be a mechanism by which maternal early life adversity is transmitted to children, especially boys. Further research is needed to determine if targeted interventions with women who have both high ACEs and mental health problems can prevent or ameliorate the effects of ACEs on children's behavioural psychopathology.
Objective
To determine the effect of disclosure of rheumatoid arthritis (RA) risk personalized with genetics, biomarkers, and lifestyle factors on health behavior intentions.
Methods
We performed a ...randomized controlled trial among first‐degree relatives without RA. Subjects assigned to the Personalized Risk Estimator for Rheumatoid Arthritis (PRE‐RA) group received the web‐based PRE‐RA tool for RA risk factor education and disclosure of personalized RA risk estimates, including genotype/autoantibody results and behaviors (n = 158). Subjects assigned to the comparison arm received standard RA education (n = 80). The primary outcome was readiness for change based on the trans‐theoretical model, using validated contemplation ladder scales. Increased motivation to improve RA risk–related behaviors (smoking, diet, exercise, or dental hygiene) was defined as an increase in any ladder score compared to baseline, assessed immediately, 6 weeks, and 6 months post‐intervention. Subjects reported behavior change at each visit. We performed intent‐to‐treat analyses using generalized estimating equations for the binary outcome.
Results
Subjects randomized to PRE‐RA were more likely to increase ladder scores over post‐intervention assessments (relative risk 1.23, 95% confidence interval 95% CI 1.01, 1.51) than those randomized to nonpersonalized education. At 6 months, 63.9% of PRE‐RA subjects and 50.0% of comparison subjects increased motivation to improve behaviors (age‐adjusted difference 15.8%; 95% CI 2.8%, 28.8%). Compared to nonpersonalized education, more PRE‐RA subjects increased fish intake (45.0% versus 22.1%; P = 0.005), brushed more frequently (40.7% versus 22.9%; P = 0.01), flossed more frequently (55.7% versus 34.8%; P = 0.004), and quit smoking (62.5% versus 0.0% among 11 smokers; P = 0.18).
Conclusion
Disclosure of RA risk personalized with genotype/biomarker results and behaviors increased motivation to improve RA risk–related behaviors. Personalized medicine approaches may motivate health behavior improvements for those at risk for RA and provide rationale for larger studies evaluating effects of behavior changes on clinical outcomes, such as RA‐related autoantibody production or RA development.
Enriching foods with long‐chain n−3 PUFA (LC n−3 PUFA) is an important approach to increasing the dietary intake of these beneficial nutrients. Enrichment of meat and eggs can be achieved by adding ...flaxseed, fish oil, or fishmeal to pig or poultry feeds. However, utilization of these sources, particularly fishmeal, has been limited by concerns about adverse effects on sensory qualities. In this study, we evaluated the use of PorcOmegaTM (POM), a stabilized tuna fishmeal formulation, as a source of DHA for enrichment of pork and poultry products. Pigs, broilers, and laying hens were fed rations containing varying levels of POM for varying time periods, and its impact on the LC n−3 PUFA content and sensory qualities of cooked meat and eggs was examined. Pork and chicken products, including chops, sausages, and eggs, with substantially increased (up to sevenfold) levels of LC n−3 PUFA (predominantly DHA) were achieved by including up to 10% POM in rations. The increases were retained after cooking. Some sensory deficits were noted when using higher levels of POM (exceeding 15% in meat and 10% in eggs). However, at modest rates of feeding (5–10% POM), palatable meat and eggs were obtained with worthwhile levels of enrichment. The fishmeal feeding strategy used in this study offers a viable means of producing a range of alternative dietary sources of LC n−3 PUFA.
•This trial compared disclosure of chronic disease risk to a standard strategy.•Personalized risk disclosure lowered concern for developing chronic disease.•Disclosing personalized chronic disease ...risk may provide reassurance to those at risk.
To investigate the effect of providing comprehensive personalized risk information on concern for chronic disease development.
Unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients (n = 238) were randomly allocated to: 1) disclosure of RA risk personalized to demographics, genetics, biomarkers, and behaviors using a web-based tool (PRE-RA arm, n = 78); 2) PRE-RA with interpretation by a health educator (PRE-RA Plus arm, n = 80); and 3) standard RA education (Comparison arm, n = 80). Concern for developing RA was assessed at baseline and immediately, 6 weeks, 6 months, and 12 months post-intervention.
FDRs randomized to PRE-RA arms were less concerned about developing RA than the Comparison arm at all post-intervention assessments (p < 0.05). Among those concerned about RA risk at baseline, the PRE-RA (OR = 4.7, 95%CI 1.5–14.4) and PRE-RA Plus (OR = 5.2, 95%CI 1.6–17.3) arms were more likely to have reassurance 6 months post-intervention than the Comparison arm.
A comprehensive tool provided reassurance to those at risk for developing a chronic disease, with or without interpretation from a health educator, compared to standard education.
Individuals may be more likely to be reassured using a personalized chronic disease risk disclosure tool than a standard non-personalized approach.
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