Biology subjects

Kaufman, D.

Publications and source records attributed to Kaufman, D..

4 recordsLinked to original sources

bioRxiv2022

Age variability and time averaging in oyster reef death assemblages

A lack of temporal context for paleoecological data from molluscan death assemblages (DAs) makes integrating them with monitoring data from living communities to inform habitat management difficult. Here we illustrate this challenge by documenting the spatial and stratigraphic variability in age and time-averaging of oyster reef death assemblages. We radiocarbon dated a total of 573 oyster shells from samples of two burial depths on 28 oyster reefs around Florida and found 1) that spatial and stratigraphic variability in DA sample ages and time-averaging are of similar magnitude, and 2) that the shallow oyster reef DAs are among the youngest and highest-resolution molluscan DAs documented to-date, with most having time-averaging estimates of decades or less. This information increases the potential usefulness of the DAs for habitat management because measured indicators can be placed in temporal context relative to monitoring data. More broadly, the results highlight the potential to obtain decadal-scale resolution from oyster bioherms in the fossil record.

paleontology↗

bioRxiv2022

GABA-receptors are a new druggable target for limiting disease severity, lung viral load, and death in SARS-CoV-2 infected mice

GABA-receptors (GABA-Rs) are well-known neurotransmitter receptors in the central nervous system. GABA-Rs are also expressed by immune cells and lung epithelial cells and GABA-R agonists/potentiators reduce inflammatory immune cell activities and limit acute lung injuries. Notably, plasma GABA levels are reduced in hospitalized COVID-19 patients. Hence, GABA-R agonists may have therapeutic potential for treating COVID-19. Here, we show that oral GABA treatment initiated just after SARS-CoV-2 infection, or 2 days later near the peak of lung viral load, reduced disease severity, lung coefficient index, and death rates in K18-hACE2 mice. GABA-treated mice had a reduced viral load in their lungs and displayed shifts in their serum cytokine and chemokine levels that are associated with better outcomes in COVID-19 patients. Thus, GABA-R activation had multiple beneficial effects in this mouse model which are also desirable for the treatment of COVID-19. A number of GABA-R agonists are safe for human use and can be readily tested in clinical trials with COVID-19 patients. We also discuss their potential for limiting COVID-19-associated neuroinflammation.

microbiology↗

bioRxiv2020

Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy

RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the RAS/MAPK pathway. In aggregate, they are among the more common Mendelian disorders. They share overlapping pathologies that include structural birth and developmental defects that affect the heart, craniofacial and skeletal, lymphatic, and nervous systems. Variants in different genes--including those encoding KRAS, NRAS, BRAF, RAF1, and SHP2--are associated with overlapping but distinct phenotypes. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human disease isoform associated with a form of RASopathy. Similar to their human counterparts, each Drosophila line has common aspects but also important phenotypic distinctions including signaling pathways as well as response to therapeutics. For some lines, these differences represent activation of pathways outside the core RAS signaling pathway including the Hippo and SAPK/JNK signaling networks. We identified two classes of clinically relevant drugs, statins and histone deacetylase inhibitors, that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved poorly effective against, e.g., SHP2-expressing lines encoded by PTPN11. Our study provides a whole animal platform for comparison of a large number of RASopathy-associated variants. Among these variants we have identified differences in tissue phenotypes, in activation signaling pathways in biomarkers of disease progression and drug efficacy, and suggest drug classes that can be tolerated over long treatment periods for consideration in broad RASopathy trials.

developmental biology↗

bioRxiv2018

Expression of a recombinant high affinity IgG Fc receptor by engineered NK cells as a docking platform for therapeutic mAbs to target cancer cells

Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy agents. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-mediated cytotoxicity (ADCC), which is a primarily effector function of NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG antibodies. Though CD16A is a potent activating receptor, it is a low affinity Fc{gamma}R and its cell surface levels can be rapidly downregulated by a proteolytic process involving ADAM17 upon NK cell activation, which are likely to limit the efficacy of tumor-targeting therapeutic mAbs in the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by engineering these cells with a recombinant Fc{gamma}R consisting of the extracellular region of CD64, the highest affinity IgG Fc receptor expressed by leukocytes, and the transmembrane and cytoplasmic regions of CD16A. This novel recombinant Fc{gamma}R (CD64/16A) was expressed in the human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells were derived. CD64/16A also lacked the ADAM17 cleavage region in CD16A and it was not rapidly downregulated in expression following NK cell activation during ADCC. CD64/16A on NK cells facilitated conjugation to antibody-treated tumor cells, ADCC, and cytokine production, demonstrating functional activity by its two components. Unlike NK cells expressing CD16A, CD64/16A captured soluble therapeutic mAbs and the modified NK cells mediated tumor cell killing. Hence, CD64/16A could potentially be used as a docking platform on engineered NK cells for therapeutic mAbs and IgG Fc chimeric proteins, allowing for switchable targeting elements, and a novel cancer cellular therapy.

immunology↗