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Biology subjects

Davis, M. T.

Publications and source records attributed to Davis, M. T..

9 recordsLinked to original sources

Prediction of transformative breakthroughs in biomedical research

The ability to predict scientific breakthroughs at scale would accelerate the pace of discovery and improve the efficiency of research investments. Recent advances in artificial intelligence, graph theory, and computing power have provided new ways to pursue this elusive goal. We have identified a common signature within co-citation networks that accurately predicts the occurrence of breakthroughs in medical research, on average more than 5 years in advance of the subsequent publication(s) that announced the discovery. A combination of features produces these diagnostic signals: a burst of papers exploring a novel scientific concept, an unusually high number of very influential papers in specialty journals, and low topical cohesion of the associated content. We analyzed two different periods separated by 20 years to show that the kinetics of breakthrough formation are conserved, suggesting that our approach can be used to predict which topics will produce future transformative discoveries. Significance statementScientific breakthroughs are rare, as is contemporaneous recognition of their initial expression. Faster, more efficient identification of topics likely to produce future breakthroughs would speed scientific and technological progress. We introduce an AI/ML-detected signature in co-citation networks that recognizes such topics up to twelve years before the breakthrough itself occurs. Our findings illustrate how a better understanding of the scientific process may lead to greater scientific returns.

scientific communication and education↗

Tcf4 Deficiency Causes Recurrent Seizures in Mice

Transcription factor 4 (TCF4) is a transcription factor that is critical for the normal development and function of the central nervous system. Haploinsufficiency of TCF4 causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures and intellectual disability. To expand our currently limited understanding of TCF4 function and PTHS pathophysiology, we created a mouse model of PTHS with largely astrocyte-specific heterozygous knockout of Tcf4. These mice developed severe recurrent seizures and had decreased lifespans. In addition, we found that these mice had astrogliosis as well as increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus. Furthermore, single nucleus RNA sequencing analysis revealed global changes in the gene expression profiles of excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes of PTHS compared to wild-type mice. Overall, this is the first report of a PTHS mouse model with seizures, providing the field with a tool to investigate the mechanisms of PTHS development and progression and develop therapeutics for PTHS and its associated epilepsy. HIGHLIGHTSO_LINovel PTHS mouse model that targets astrocytes develops epilepsy C_LIO_LIPTHS mice exhibit astrogliosis and increased neuron activity C_LIO_LIChanges in gene expression profile observed in PTHS mice across neurons and glial cells C_LI

neuroscience↗

Convergent evolution of epigenome recruited DNA repair across the Tree of Life

Mutations fuel evolution while also causing diseases like cancer. Epigenome-targeted DNA repair can help organisms protect important genomic regions from mutation. However, the adaptive value, mechanistic diversity, and evolution of epigenome-targeted DNA repair systems across the tree of life remain unresolved. Here, we investigated the evolution of histone reader domains fused to the DNA repair protein MSH6 (MutS Homolog 6) across over 4,000 eukaryotes. We uncovered a paradigmatic example of convergent evolution: MSH6 has independently acquired distinct histone reader domains; PWWP (metazoa) and Tudor (plants), previously shown to target histone modifications in active genes in humans (H3K36me3) and Arabidopsis (H3K4me1). Conservation in MSH6 histone reader domains shows signatures of natural selection, particularly for amino acids that bind specific histone modifications. Species that have gained or retained MSH6 histone readers tend to have larger genome sizes, especially marked by significantly more introns in genic regions. These patterns support previous theoretical predictions about the co-evolution of genome architectures and mutation rate heterogeneity. The evolution of epigenome-targeted DNA repair has implications for genome evolution, health, and the mutational origins of genetic diversity across the tree of life. Short SummaryFusions between histone reader domains and the mismatch repair protein MSH6 have evolved multiple times across Eukaryotes and show evidence of selection, providing mechanistic and theoretical insight into the forces shaping genomic mutation rate heterogeneity.

evolutionary biology↗

Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation

(ii) ABSTRACTO_ST_ABSAimsC_ST_ABSAtrial fibrillation (AFib) is the most common cardiac rhythm disturbance. Treatment of AFib involves restoration of the atrial electrical rhythm. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs that involves decreased blood flow velocity and reduced atrial contractility. This suggests that defects in contractility occur in AFib and are revealed upon restoration of rhythm. The aim of this project is to define the contractile remodeling that occurs in AFib Methods and ResultsTo assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared to sinus rhythm atria. Atrial cardiomyocytes showed reduced force of contraction in skinned single cardiomyocyte calcium-force studies. There were no significant differences in myosin heavy chain isoform expression. Resting tension is decreased in the AFib samples correlating with reduced full-length titin in the sarcomere. We measured degradation of other myofilament proteins including cMyBP-C, actinin, and cTnI, showing significant degradation in the AFib samples compared to sinus rhythm atria. Many of the protein degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. Skinned cardiomyocytes from AFib atria showed decreased troponin I phosphorylation, consistent with the increased calcium sensitivity that was found within these cardiomyocytes. ConclusionsWith these results it can be concluded that AFib causes alterations in contraction that can be explained by both molecular changes occurring in myofilament proteins and overall myofilament protein degradation. These results provide an understanding of the contractile remodeling that occurs in AFib and provides insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib.

cell biology↗

Oxytocin receptor antagonism during song tutoring in zebra finches reduces preference for and learning of the tutor's song

In species with vocal learning, acquiring species-typical vocalizations relies on early social orienting. In zebra finches (Taeniopygia guttata), for example, learning song requires dynamic social interactions with a "tutor" during an early sensitive period. The oxytocin system plays a central role in social orienting across species, yet it is unknown whether this system participates in the attentional and motivational processes that support vocal learning. Here, we tested whether blocking oxytocin receptors during exposure to tutors would impact learning from those tutors. Juvenile, song-naive males were each tutored by two unfamiliar adults. During exposure to one tutor, juveniles were treated with oxytocin receptor antagonist (OTA) and during exposure to the other, saline (control). We found that OTA significantly reduced behaviors associated with approach and attention during tutoring sessions. Next, using an operant assay in which exposure to the two songs was balanced, we found that the juveniles preferred the control song over the OTA song. The developmental trajectory of preference for the control song resembled the pattern shown by father-reared birds choosing to hear their fathers song. Finally, the adult songs of the tutored birds more closely resembled control song than OTA song. The magnitude of this difference was significantly predicted by the early preference for the control song. Overall, oxytocin antagonism during exposure to a tutor seemed to bias juveniles against that tutor and his song. Our results suggest that oxytocin receptors play a role in socially-guided vocal learning in zebra finches, perhaps by affecting attention and motivation during tutoring.

animal behavior and cognition↗

The effect of mentee and mentor gender on scientific productivity of applicants for NIH training fellowships

Several studies have suggested that women in science are less productive than men, and that this gap contributes to their under-representation in the ranks of senior researchers. However, few studies have examined the role of mentoring, and in particular mentor gender, on the productivity of female scientists early in their careers. Such efforts are limited by the difficulties of unambiguously linking mentees to their mentors and measuring the research productivity resulting from those relationships. Here we use our novel author disambiguation solution to investigate the role of self-identified gender in mentorship of 12,932 trainees who either successfully or unsuccessfully applied to the National Institutes of Health for research fellowships between fiscal years 2011 and 2017, applying a multi-dimensional framework to assess productivity. We found that, after normalizing for the funding level of mentors, the productivity of female and male mentees is indistinguishable; it is also independent of the gender of the mentor, other than in measures of clinical impact, where women mentored by women outperform other mentee-mentor dyads.

scientific communication and education↗

Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation

Maternal immune activation (MIA) increases likelihood of altered neurodevelopmental outcomes. Maternal cytokines are proposed to affect fetal brain development in mice; however, the contribution of fetal immunity to neurodevelopmental disorders is largely unexplored. Here, we show that MIA mediated by Toll-like receptor 3 (TLR3), but not other TLRs, induces a specific set of behavioral phenotypes including decreased sociability and increased restricted repetitive behavior in offspring. Accordingly, these behavioral phenotypes were absent when offspring were deficient for Trif, the downstream adapter molecule of TLR3. Using single-cell RNA sequencing, we identified clusters of border-associated macrophages that were significantly enriched in the fetal brain following TLR3-MIA, and these clusters were diminished in Trif-/- fetal brains.Moreover, we found that triggering TLR3-TRIF in offspring can occur through transplacental viral infection, resulting in altered behavioral phenotypes. Collectively, our data indicate that fetal innate immunity contributes to MIA-induced atypical behaviors in mice.

neuroscience↗

Detecting genes associated with pathogenicity and antimicrobial resistance in three New Zealand waterways.

BO_SCPLOWACKGROUNDC_SCPLOWMore than 100 zoonoses may be transmitted via water, among them enteric diseases are leading causes of human mortality. Traditional monitoring for zoonoses relies on culturing of indicator species, but environmental DNA (eDNA) provides an alternative, allowing direct testing for genetic loci associated with pathogenicity and/or antimicrobial resistance in zoonotic bacteria. OO_SCPLOWBJECTIVESC_SCPLOWTo evaluate whether genes associated with Shiga toxin producing Escherichia coli (STEC) and antimicrobial resistance can be monitored in waterways using culture-free sampling of eDNA combined with PCR-based testing. MO_SCPLOWETHODSC_SCPLOWWater and sediment samples were collected from two sites on each of three rivers in Canterbury, New Zealand; sample sites were situated above and below reaches bordered by intensive dairy farming. Samples from each site were tested for genes typically associated with Escherichia coli, STEC serogroups O26 and O157, human pathogenic strains of STEC, and resistance to a broad range of antibiotics. RO_SCPLOWESULTSC_SCPLOWBoth culturing and genetic testing confirmed the presence of E. coli in all samples. In contrast, presence of genes associated with STEC and antibiotic resistance varied by season and substrate. The O157 serogroup was identified at more than twice as many sites as O26, with the latter more common in autumn samples. In autumn, genes associated with pathogenic STEC were detected in one Ashley and both Rangitata River samples but were present in all spring samples, except one Ashley and one Selwyn River collection. The antibiotic resistance gene was only identified in spring, predominantly at sites downstream of intensive dairying. DO_SCPLOWISCUSSIONC_SCPLOWWhile our sample is small this study indicates that genetic testing of eDNA can be a useful tool for monitoring the presence and persistence of zoonoses in waterways. How the presence of these genetic elements is related to that of pathogenic STEC and incidence of disease in humans now needs to be examined.

ecology↗

Expression of oxytocin receptors in the zebra finch brain during vocal development

Juvenile male zebra finches memorize and learn to sing the song of a male caregiver, or \"tutor\", during a complex vocal learning process. Juveniles are highly motivated to interact socially with their tutor, and these interactions are required for effective vocal learning. It is currently unknown what neurological mechanisms underlie attraction to tutors, but social motivation and affiliation in this and other species may be mediated by oxytocin and related nonapeptides. Here, we used qPCR to quantify expression of oxytocin receptor (OTR) mRNA in the lateral septum, auditory forebrain, and regions of the song control system in zebra finches throughout post-hatch development and vocal learning. We found that zebra finches express OTR mRNA in these regions from post-hatch day 5 to adulthood, encompassing the entire period of auditory and sensorimotor learning. We also mapped the binding of 125I-ornithine vasotocin, an oxytocin receptor antagonist that binds to oxytocin receptors in songbird brain, to understand the neuroanatomical distribution of oxytocin-like action during vocal development. This study provides the groundwork for the use of zebra finches as a model for understanding the mechanisms underlying social motivation and its role in vocal development.

neuroscience↗