Biology subjects

de la Fuente, A.

Publications and source records attributed to de la Fuente, A..

4 recordsLinked to original sources

bioRxiv2022

Deletion of TRPC6, an autism risk gene, induces hyperexcitability in cortical neurons derived from human pluripotent stem cells

Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder linked to numerous rare, inherited and arising de novo genetic variants. ASD often co-occurs with attention-deficit hyperactivity disorder and epilepsy, which are associated with hyperexcitability of neurons. However, the physiological and molecular mechanisms underlying hyperexcitability in ASD remain poorly understood. Transient receptor potential canonical-6 (TRPC6) is a Ca2+-permeable cation channel that regulates store-operated calcium entry (SOCE) and is a candidate risk gene for ASD. Using human pluripotent stem cell (hPSC)-derived cortical neurons, single cell calcium imaging, and electrophysiological recording, we show that TRPC6 knockout (KO) reduces SOCE signaling and leads to hyperexcitability of neurons by increasing action potential frequency and network burst frequency. Our data provide evidence that reduction of SOCE by TRPC6 KO results in neuronal hyperexcitability, which we hypothesize is an important contributor to the cellular pathophysiology underlying hyperactivity in some ASD.

neuroscience↗

bioRxiv2022

Changes in gamma bursts supporting working memory development through adolescence derived from EEG spectral processing

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, it did not appear to change during the delay period resulting in an increasing difference between the number of events during fixation and delay period with development, suggesting that as working memory develops there is greater specificity for gamma events supporting working memory. While average power of the transient gamma events was found to mediate age-related changes in total gamma power, the number of gamma events was unrelated to total power, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.

neuroscience↗

bioRxiv2021

Long-term changes in populations of rainforest birds in the Australia Wet Tropics bioregion: a climate-driven biodiversity emergency

Many authors have suggested that the vulnerability of montane biodiversity to climate change worldwide is significantly higher than in most other ecosystems. Despite the extensive variety of studies predicting severe impacts of climate change globally, few studies have empirically validated the predicted changes in distribution and population density. Here, we used 17 years of bird monitoring across latitudinal/elevational gradients in the rainforest of the Australian Wet Tropics World Heritage Area to assess changes in local abundance and distribution. We used relative abundance in 1977 surveys across 114 sites ranging from 0-1500m above sea level and utilised a trend analysis approach (TRIM) to investigate elevational shifts in abundance of 42 species between 2000 - 2016. The local abundance of most mid and high elevation species has declined at the lower edges of their distribution by >40% while lowland species increased by up to 190% into higher elevation areas. Upland-specialised species and regional endemics have undergone dramatic population declines of almost 50%. The "Outstanding Universal Value" of the Australian Wet Tropics World Heritage Area, one of the most irreplaceable biodiversity hotspots on Earth, is rapidly degrading. These observed impacts are likely to be similar in many tropical montane ecosystems globally.

ecology↗

bioRxiv2020

Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity -- opportunity for repurposed chemotherapy of COVID-19 infection

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produced an urgent requirement and search for improved treatments whilst effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. For arginine residues of the SARS-CoV-2 predicted to be in functional domains, we examined which are activated towards modification by MG - residues with predicted or expected low pKa by neighbouring group in interactions. We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae: SARS-COV and MERS. Finally, we identified drugs which increase cellular MG concentration to virucidal levels: antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established.

biochemistry↗