The specific immune response in rainbow trout: Somatic hypermutation and VH gene utilization

The study of antibody responses in prominent aquaculture species such as the rainbow trout, Oncorhynchus mykiss, can facilitate vaccine development and contribute to producing useful paradigms of adaptive immunity in lower vertebrates. Thus, it is essential to identify genes responsible for antibody responses. In the mouse model, hybridoma technology allows for the association of monoclonal antibodies possessing various affinities for antigen with specific VH sequences, gene family utilization, and other molecular events (i.e. somatic hypermutation) that occur during the specific immune response. The absence of a comparable hybridoma technology in piscine systems has limited similar studies of fish immunogenetics to date. Molecular and serological experiments were performed in an attempt to obtain information regarding somatic mutation and VH gene utilization for trout antibodies without reliance on hybridoma technology. PCR primers recognizing consensus sequences of FR1 and FR3 were used to amplify antibody VH sequences from panned, antigen-specific B cells. to follow the development of the expressed VH repertoire, lymphocytes were obtained at weeks 0, 5, 10, and 20 post primary immunization with trinitrophenylated-keyhole limpet hemocyanin (TNP-KLH) or infectious hematopoietic necrosis virus (IHNV). Lymphocytes were also collected 10 weeks post secondary immunization (week 35). These studies were conducted in parallel with serological analyses of plasma antibodies obtained from the same sample in order to correlate molecular data with serological data from individual trout. Antigen-specific lymphocytes were processed to isolate RNA templates to produce cDNA which was cloned and sequenced. This sequence analysis allowed us to report, for the first time, the temporal accumulation of potential somatic variants that correlate to the development of new, high affinity antibody subpopulations during the immune response, some with the emergence of new antibody heavy chain isoelectropherotypes as identified by 2D-IEF/SDS-PAGE. Southern analysis and gene titration using various antigen-specific cDNA probes allowed us to correlate trout antibodies possessing various affinities for antigen with specific VH sequence and gene family utilization. Thus, trout Ig VH gene family utilization appears to follow the mouse model of differential use for specific immune response. These results reveal a capability for fine-tuning the piscine immune response previously not recognized

Talactoferrin Immunotherapy in Metastatic Renal Cell Carcinoma: A Case Series of Four Long-Term Survivors

Talactoferrin alfa (also known as recombinant human lactoferrin, rhLF) is a novel immunomodulatory protein that has previously demonstrated anti-tumor properties in animal models. Following a successful phase I trial, it was administered orally to patients with metastatic renal cell carcinoma (RCC) in a phase II trial conducted at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, among other sites. We report a case series of 4 patients treated at our institution with very encouraging progression-free survivals, all exceeding 30 months, in order to suggest that this agent merits further study. These four patients with radiographically progressive metastatic RCC received single-agent oral talactoferrin in daily doses of 9 grams, given in cycles of 2 weeks on/2 weeks off, until evidence of toxicity or disease progression. Given the small sample size and the heterogenous tumor biology of RCC, tumor growth rate was used as a primary endpoint so that each patient could serve as their own control. The agent's effectiveness was then determined through radiographic tracking of the tumors before, during, and after treatment, with use of the Response Evaluation Criteria in Solid Tumors (RECIST) protocol to follow target lesions. The results showed that the drug was well tolerated, with no occurrence of talactoferrin-related grade 3 or 4 adverse events or laboratory anomalies by NCI-CTEP criteria. The four patients described in the case series demonstrated very encouraging progression-free survivals, all exceeding 30 months. We conclude that decreased tumor growth rate may correlate with increased progression-free survival. Talactoferrin is a promising, well-tolerated agent whose clinical benefits should be evaluated in a randomized phase III study with a placebo control arm

Dynamics of Dengue epidemics using optimal control

We present an application of optimal control theory to Dengue epidemics. This epidemiologic disease is an important theme in tropical countries due to the growing number of infected individuals. The dynamic model is described by a set of nonlinear ordinary differential equations, that depend on the dynamic of the Dengue mosquito, the number of infected individuals, and the people's motivation to combat the mosquito. The cost functional depends not only on the costs of medical treatment of the infected people but also on the costs related to educational and sanitary campaigns. Two approaches to solve the problem are considered: one using optimal control theory, another one by discretizing first the problem and then solving it with nonlinear programming. The results obtained with OC-ODE and IPOPT solvers are given and discussed. We observe that with current computational tools it is easy to obtain, in an efficient way, better solutions to Dengue problems, leading to a decrease of infected mosquitoes and individuals in less time and with lower costs.Comment: Submitted to Mathematical and Computer Modelling 25/Oct/2009; accepted for publication, after revision, 22/June/201

Two-year follow-up of macaques developing intermittent control of the human immunodeficiency virus homolog simian immunodeficiency virus SIVmac251 in the chronic phase of infection

Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4(+) T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir

Nonprofit Trends and Impacts 2021: National Findings on Donation Trends from 2015 through 2020, Diversity and Representation, and First-Year Impacts of the COVID-19 Pandemic

Nonprofit organizations in the United States play a vital role delivering services, strengthening communities, and facilitating civic engagement. They are diverse in size and type, ranging from all-volunteer organizations with no revenue to multibilliondollar institutions managed by highly professionalized staff. They have diverse revenue sources, including individual donors, fees for service, and public and private institutions. Though research has illuminated much about these organizations in recent years, we lack a nationally representative portrait of the nonprofit sector detailing donation trends and who is served, where, and by whom. Our nationally representative study fills these gaps.We focus on operating 501(c)(3) public charities whose activities range from direct service provision to community building and advocacy. We exclude many service providers in specialized fields, including hospitals, schools, higher-education institutions, churches, and other houses of worship, and we exclude organizations that usually fund other organizations rather than providing services directly. This report complements studies on donation trends conducted from individual donor and sector-wide perspectives by focusing on the experiences of nonprofits, donations that they rely on, the contexts and contours of their programs, and the US communities they serve.

Application of ¹⁴C analyses to source apportionment of carbonaceous PM_2.5 in the UK

Determination of the radiocarbon (<sup>14</sup>C) content of airborne particulate matter yields insight into the proportion of the carbonaceous material derived from fossil and contemporary carbon sources. Daily samples of PM<sub>2.5</sub> were collected by high-volume sampler at an urban background site in Birmingham, UK, and the fraction of <sup>14</sup>C in both the total carbon, and in the organic and elemental carbon fractions, determined by two-stage combustion to CO<sub>2</sub>, graphitisation and quantification by accelerator mass spectrometry. OC and EC content was also determined by Sunset Analyzer. The mean fraction contemporary TC in the PM<sub>2.5</sub> samples was 0.50 (range 0.27–0.66, n = 26). There was no seasonality to the data, but there was a positive trend between fraction contemporary TC and magnitude of SOC/TC ratio and for the high values of these two parameters to be associated with air-mass back trajectories arriving in Birmingham from over land. Using a five-compartment mass balance model on fraction contemporary carbon in OC and EC, the following average source apportionment for the TC in these PM<sub>2.5</sub> samples was derived: 27% fossil EC; 20% fossil OC; 2% biomass EC; 10% biomass OC; and 41% biogenic OC. The latter category will comprise, in addition to BVOC-derived SOC, other non-combustion contemporary carbon sources such as biological particles, vegetative detritus, humic material and tyre wear. The proportion of total PM<sub>2.5</sub> at this location estimated to derive from BVOC-derived secondary organic aerosol was 9–29%. The findings from this work are consistent with those from elsewhere in Europe and support the conclusion of a significant and ubiquitous contribution from non-fossil biogenic sources to the carbon in terrestrial aerosol

Novel High Capacity Oligomers for Low Cost CO2 Capture

The novel concept of using a molecule possessing both physi-sorbing and chemi-sorbing properties for post-combustion CO2 capture was explored and mixtures of aminosilicones and hydroxyterminated polyethers had the best performance characteristics of materials examined. The optimal solvent composition was a 60/40 blend of GAP-1/TEG and a continuous bench-top absorption/desorption unit was constructed and operated. Plant and process models were developed for this new system based on an existing coal-fired power plant and data from the laboratory experiments were used to calculate an overall COE for a coal-fired power plant fitted with this capture technology. A reduction in energy penalty, from 30% to 18%, versus an optimized 30% MEA capture system was calculated with a concomitant COE decrease from 73% to 41% for the new aminosilicone solvent system

Giant multicaloric response of bulk Fe49Rh51

We report on the multicaloric response of the Fe49Rh51 alloy under the combined application of hydrostatic pressure and magnetic field. Experimental data are complemented by a mean field model that takes into account the interplay between structural and magnetic degrees of freedom. A large multicaloric strength has been found for this alloy, and it is shown that a suitable combination of pressure and magnetic field enables the sign of the entropy change to be reversed and thus the multicaloric effect can be tuned from conventional to inverse. It is also shown that an extended temperature window for the multicaloric effect can be achieved by taking advantage of the coupling between structure and magnetism which enables a cross response of the alloy under the application of different external fields. Mean field calculations remarkably reproduce experimental results

Key Data Gaps for Understanding Trends in Prescription Opioid Analgesic Abuse and Diversion Among Chronic Pain Patients and Nonmedical Users

Population dynamics of medical and nonmedical prescription opioid usage and adverse outcomes were modeled. Critical parameter values were determined by their amount of influence on model behavior. Results suggest that closing these data gaps would help researchers to better identify ways to reduce the risk of adverse outcomes