Biology subjects

Adams, S.

Publications and source records attributed to Adams, S..

25 records · Page 2Linked to original sources

bioRxiv2020

Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFN{gamma}). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFN{gamma} activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFN{gamma} not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFN{gamma} reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53-/- ovarian carcinoma mouse model. The combined MPLA+IFN{gamma} treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor (TNF). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFN{gamma}. MPLA and IFN{gamma} are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.

cancer biology↗

bioRxiv2020

Orthotopic Transplantation and Engraftment of Human Induced Pluripotent Stem Cell-Derived Alveolar Progenitor Cells into Murine Lungs

Humanized mice possessing human cells, tissues, or organ systems provide an unparalleled platform for preclinical studies in oncology, immunology, and infectious diseases. While the lungs are a vital organ subject to a wide variety of pathologies, exemplified by the ongoing COVID-19 pandemic, discrete differences in murine and human lungs can obfuscate interpretation of murine models of lung disease. Here we provide proof-of-concept methodology for the potential humanization of murine lungs via orthotopic transplantation of human NKX2.1+ progenitor cells and alveolar type 2 cells derived from induced pluripotent stem cells. We show that these cells engraft readily into highly immunocompromised mice after pharmacological injury with bleomycin, which presumably generates "space" for human cells to access denuded basement membrane and engraft. Transplanted cells stably retain their pulmonary lineage restriction and persist as superficially differentiated alveolar type 2 and type 1 cells. Future work should focus on strategies to promote xenorepopulation of most / all of the murine lung with human cells while retaining appropriate regio-specific epithelial differentiation and normal physiological function.

developmental biology↗

bioRxiv2020

The Ancient DNA Insights into Aboriginal Australian Mortuary Practices

Paleogenetics is a relatively new and promising field that has the potential to provide new information about past Indigenous social systems, including insights into the complexity of burial practices. We present results of the first ancient DNA (aDNA) investigation into traditional mortuary practices among Australian Aboriginal people with a focus on North-East Australia. We recovered mitochondrial and Y chromosome sequences from five ancestral Aboriginal Australian remains that were excavated from the Flinders Island group in Cape York, Queensland. Two of these individuals were sampled from disturbed beach burials, while the other three were from bundle burials located in rock shelters. Genomic analyses showed that individuals from all three rock shelter burials and one of the two beach burials had a close genealogical relationship to contemporary individuals from communities from Cape York. In contrast the remaining male individual, found buried on the beach, had a mitochondrial DNA sequence that suggested that he was not from this location but that he was closely related to people from central Queensland or New South Wales. In addition, this individual was associated with a distinctive burial practice to the other four people. It has been suggested that traditionally non-locals or lower status individuals were buried on beaches. Our findings suggest that theories put forward about beach burials being non-local, or less esteemed members of the community, can potentially be resolved through analyses of uniparental genomic data. Generally, these results support the suggestion often derived from ethnohistoric accounts that inequality in Indigenous Australian mortuary practices might be based on the status, sex, and/or age of individuals and may instead relate to place of geographic origin. There is, however, some departure from the traditional ethnohistoric account in that complex mortuary internments were also offered to female individuals of the community, with genomic analyses helping to confirm that the gender of one of the rockshelter internments was that of a young female.

evolutionary biology↗

bioRxiv2018

Effects of varenicline and cognitive bias modification on neural response to smoking-related cues: a randomised control trial

Drug-related cognitive biases have been positively associated with drug-craving and increased likelihood of relapse. Cognitive bias modification paradigms have been developed to attenuate cognitive biases but there have been few studies that examined neural responses to these paradigms. This study compared neural responses following CBM and explored whether CBM effects were potentiated by varenicline administration. This was a double-blind placebo-controlled study with two between subject factors of drug (varenicline, placebo) and CBM (attend towards smoking cues, train away from smoking cues, control training) that recruited daily ([≥] 10 cigarettes per day) non-treatment seeking smokers. Participants (n = 67, 53% female) were randomised to one-week of drug administration (varenicline or placebo) before attending a study session at which they were randomised to CBM condition, and underwent an fMRI scan were they were presented with smoking and neutral cues. Neural response to smoking (vs. neutral) cues, cognitive bias, craving and mood were assessed. There was no evidence of CBM effects on any outcomes. There was evidence of effects of varenicline on craving, with greater reductions in craving in the week preceding the study session in the varencline group (p = 0.04,{eta} p2 = .06). There was also evidence of a drug by CBM interaction for neural responses (z = 3.78, p <0.001). Compared to placebo, varenicline was associated with greater activation in the right temporal middle gyrus in the CBM control condition, compared to an opposite effect in the CBM \"attend towards\" condition. These data suggest that CBM does not modify cognitive bias, subjective craving and mood, or neural response to smoking cues. There was also no evidence that CBM effects were potentiated by varenicline.

clinical trials↗

bioRxiv2018

Chromosome-wide evolution and sex determination in a nematode with three sexes

The free-living nematode Auanema rhodensis is a rare example of a species with three sexes, in which males, females and hermaphrodites coexist. A. rhodensis males have only one X chromosome (XO), whereas females and hermaphrodites have two (XX). The A. rhodensis X chromosome is unusual: it does not recombine in hermaphrodites and is transmitted from father to son. The mechanism that controls the production of females versus hermaphrodites is unknown but is dependent on maternal and larval environmental factors. Here we report the genome sequence and genetic map of A. rhodensis, placing over 95% of the sequence in seven linkage groups. Comparison of the seven A. rhodensis chromosomes to chromosomal assemblies of Caenorhabditis elegans and three other rhabditine nematodes identified deeply conserved linkage groups we call Nigon units, some of which have been maintained in all species analysed. Others have undergone breakage and fusion, and the A. rhodensis karyotype is the product of a unique set of rearrangements involving three Nigon units. The A. rhodensis X chromosome is much smaller than the autosomes, is less gene dense and is 3 to 4 times more polymorphic, reflecting its unique transmission history. Differential expression analyses comparing females and hermaphrodites, identified several candidate genes, including orthologues of C. elegans gld-1, tra-1 and dmd-10/11, that are potentially involved in the female-hermaphrodite sexual decision.

genetics↗

bioRxiv2018

Liposome-based transfection enhances RNAi and CRISPR-mediated mutagenesis in non-model nematode systems

Nematodes belong to one of the most diverse animal phyla. However, functional genomic studies in nematodes, other than in a few species, have often been limited in their reliability and success. Here we report that by combining liposome-based technology with microinjection, we were able to establish a wide range of genomic techniques in the newly described nematode genus Auanema. The method also allowed heritable changes in dauer larvae of Auanema, despite the immaturity of the gonad at the time of the microinjection. As proof of concept for potential functional studies in other nematode species, we also induced RNAi in the free-living nematode Pristionchus pacificus and targeted the human parasite Strongyloides stercoralis.

developmental biology↗

bioRxiv2018

Emotional recognition training modifies neural response to emotional faces but does not improve mood in healthy volunteers with high levels of depressive symptoms

IMPORTANCEDepression is a debilitating and highly prevalent mental health disorder. There is a need for new, effective, and scalable treatments for depression, and cognitive bias modification (CBM) of negative emotional processing biases has been suggested as one possibility. Such treatments may form the basis of digital therapeutics, that could be administered remotely and at low cost, should they prove to be effective.\n\nOBJECTIVESStudy one was designed to determine neural correlates of a recently developed CBM technique for emotion recognition training; specifically, our aim was to compare the effects of training vs placebo on pre-specified regions of interest involved in emotion processing that are known to be sensitive to antidepressant treatment. Study two aimed to investigate efficacy of training on mood measures at 2 and 6-week follow-up and was powered to replicate and extend earlier findings.\n\nDESIGN, SETTING, AND PARTICIPANTSBoth studies were double blind RCTs, in which participants completed five sessions of emotion recognition training or sham training, in the laboratory, over a one-week period. In study one (N=37), following this training, participants completed a novel emotion recognition task whilst undergoing fMRI. In study two (N=190), measures of mood were assessed post training, and at 2-week and 6-week follow-up. Both studies recruited analogue samples of healthy volunteers with high levels of depressive symptoms (BDI-ii > 14).\n\nMAIN OUTCOMES AND MEASURESIn study one, our primary outcome was neural activation in the following pre-specified regions of interest: the bilateral amygdala, the mPFC, bilateral dlPFC, and the occipital cortex. In study two, our primary outcome was depressive symptoms over the last 2 weeks assessed using the BDI-ii at 6-week follow-up. Secondary outcomes included depressive symptoms measured using the HAM-D, and positive and negative affect assessed using the PANAS.\n\nRESULTSIn both studies, CBM resulted in a change in emotion recognition bias, which (in study two) persisted for 6 weeks after the end of the CBM phase. In study one, CBM resulted in increases neural activation to happy faces compared to sad faces, with this effect driven by an increase in neural activity for happy faces. We saw this increase in activation for this contrast at both the whole brain level and among our a priori ROIs, specifically the mPFC and bilateral amygdala. In study two, CBM did not lead to a reduction in depressive symptoms on the BDI-ii, or on related measures of mood, motivation and persistence, or depressive interpretation bias.\n\nCONCLUSIONS AND RELEVANCECBM of emotion recognition appears to have effects on neural activity that are similar in some respects to those induced by SSRI administration (study one), but we find no evidence that this has any effect on self-reported mood in an analogue sample of healthy volunteers with low mood (study two).

neuroscience↗