Biology subjects

Rodriguez, A.

Publications and source records attributed to Rodriguez, A..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Structural basis of flagellar filament asymmetry and supercoil templating by Leptospira spirochete sheath proteins

Several Leptospira species are bacterial agents of leptospirosis, a neglected tropical disease responsible for ~1 million cases and 50,000 deaths each year worldwide. Leptospira, like other members of the Spirochaeta phylum, possess specially adapted flagella that remain confined within the periplasm. These appendages drive a unique, corkscrew-like swimming style that enables efficient motility and pathogenesis. However, the composition, function, and molecular architecture of spirochetal flagellar filaments remain poorly understood. We solved single-particle cryo-EM structures of isolated Leptospira flagellar filaments, comparing the wild-type form to two mutant forms with different missing components and abrogated motilities. The structures reveal a complex proteinaceous sheath surrounding a conserved core composed of the FlaB flagellin homolog. Sheath proteins were found to fall into two distinct categories, both of which are required for motility. Filament coiling proteins, FcpA and FcpB, exert force on the filament when they bind its surface, causing the filament to stretch. In contrast, we identify sheath components FlaAP (newly discovered in this study) and FlaA2 as template factors, which have little effect on filament shape by themselves, but partition the coiling proteins to one side of the filament. In this way, the two types of Leptospira sheath factors operate collectively on the flagellar filament to bend it from a relaxed form associated with cell immobility, to a motility-competent shape that is tightly supercoiled. Our structures also indicate that core-sheath interactions are largely mediated by carbohydrate moieties from flagellin core side chain O-glycosylations. The supercoiling mechanism presented here provides a benchmark for studies with other bacteria, for which near-atomic resolution structures of flagellar filament in native supercoiled forms, are still lacking.

biophysics↗

bioRxiv2021

Novel Fusarium Wilt Resistance Genes Uncovered in the Wild Progenitors and Heirloom Cultivars of Strawberry

Fusarium wilt, a soilborne disease caused by Fusarium oxysporum f. sp. fragariae, poses a significant threat to strawberry (Fragaria x ananassa) production in many parts of the world. This pathogen causes wilting, collapse, and death in susceptible genotypes. We previously identified a dominant gene (FW1) on chromosome 2B that confers resistance to race 1 of the pathogen and hypothesized that gene-for-gene resistance to Fusarium wilt was widespread in strawberry. To explore this, a genetically diverse collection of heirloom and modern cultivars and wild octoploid ecotypes were screened for resistance to Fusarium wilt races 1 and 2. Here we show that resistance to both races is widespread and that resistance to race 1 is mediated by dominant genes (FW1, FW2, FW3, FW4, and FW5) on three non-homoeologous chromosomes (1A, 2B, and 6B). The resistance proteins encoded by these genes are not yet known; however, plausible candidates were identified that encode pattern recognition receptor or other proteins known to mediate gene-for-gene resistance in plants. High-throughput genotyping assays for SNPs in linkage disequilibrium with FW1-FW5 were developed to facilitate marker-assisted selection and accelerate the development of race 1 resistant cultivars. This study laid the foundation for identifying the genes encoded by FW1-FW5, in addition to exploring the genetics of resistance to race 2 and other races of the pathogen, as a precaution to averting a Fusarium wilt pandemic. Key MessageSeveral race-specific resistance genes were identified and rapidly deployed via marker-assisted selection to develop strawberry cultivars resistant to Fusarium wilt, a devastating soil-borne disease.

plant biology↗

bioRxiv2021

Harbingers of Aggressive Prostate Cancer: Precision Oncology Case Studies

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intra-tumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (nine patients). Activating AR alterations were seen in eight (67%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the "index" primary PCa area.

cancer biology↗

bioRxiv2021

Effect of landscape structure on genetic structure of the Lesser horseshoe bat (Rhinolophus hipposideros) in Britanny colonies

Some species are difficult to observe and others, need to be not disturbed because of their vulnerability. In response to the difficulty of studying the dispersal behaviors of these species, some areas of biology have been combined in order to access the information despite practical limitations. Here we present the combination of several methodologies from landscape ecology to non- invasive population genetics that allow us to obtain important information on Rinolophus hipposideros, a vulnerable European bat. We genotyped 18 georeferrenced colonies in Brittany (France) from droppings collected in their refuges. We used 6 microsatellite markers in order to obtain the genetic distances between them. On the other hand we calculated Euclidian distances between the refuges occupied by these colonies and some ecological distances with the Pathmatrix module of ArcGis 3.2. We tested hypothesis about the difficulty of dispersal of the species in areas without forest cover or with a low density of hedges. Thanks to the Monmonier algorithm we could infer possible genetic barriers between the colonies and we could compare their location to the presence of landscape barriers (areas with little tree cover). We detected a pattern of isolation by distance that reveals limited dispersal capacities in the species but no pattern linked to ecological distances. We found that some of the neighboring colonies with greater genetic distances between them were located in areas with low density of hedges which could suggest an impact of this landscape element in their movements. Finer studies should allow us to conclude on the need or not of forest cover in the dispersal of this species. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/470144v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1efb190org.highwire.dtl.DTLVardef@17287c8org.highwire.dtl.DTLVardef@3072c7org.highwire.dtl.DTLVardef@bf84a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2021

A Complete Pedigree-Based Graph Workflow for Rare Candidate Variant Analysis

Methods that use a linear genome reference for genome sequencing data analysis are reference biased. In the field of clinical genetics for rare diseases, a resulting reduction in genotyping accuracy in some regions has likely prevented the resolution of some cases. Pangenome graphs embed population variation into a reference structure. While pangenome graphs have helped to reduce reference mapping bias, further performance improvements are possible. We introduce VG-Pedigree, a pedigree-aware workflow based on the pangenome-mapping tool of Giraffe (Siren et al. 2021) and the variant-calling tool DeepTrio (Kolesnikov et al. 2021) using a specially-trained model for Giraffe-based alignments. We demonstrate mapping and variant calling improvements in both single-nucleotide variants (SNVs) and insertion and deletion (INDEL) variants over those produced by alignments created using BWA-MEM to a linear-reference and Giraffe mapping to a pangenome graph containing data from the 1000 Genomes Project. We have also adapted and upgraded the deleterious-variant (DV) detecting methods and programs of Gu et al. into a streamlined workflow (Gu et al. 2019). We used these workflows in combination to detect small lists of candidate DVs among 15 family quartets and quintets of the Undiagnosed Diseases Program (UDP). All candidate DVs that were previously diagnosed using the mendelian models covered by the previously published Gu et al. methods were recapitulated by these workflows. The results of these experiments indicate a slightly greater absolute count of DVs are detected in the proband population than in their matched unaffected siblings.

bioinformatics↗

bioRxiv2021

Differences in personality / temperament in the endangered tortoise Testudo hermanni and their implications on dispersal and conservation

Behavioural studies are more an more implicated in species conservation. Determining individuals personality in the case of reintroduction operations may be very useful. Actually, indiviuals temperament may be associated to their dispersal capacities and their habilities to adapt to novel environments. Considered as asociable species, few studies have been conducted on reptiles and this is even worse in the case of endangered species. Hermann tortoise, Testudo hermanni, an endemic species from Mediterranean region is endangered because of the lost and modification of its habitats. Before conducting reintroduction actions it is important to have more information on individuals personality traits. We have tested the reaction of three groups of tortoises (domestic, wild and from the SOPTOM center) when confronted to a novel environment and to human presence. The aim was to discriminate individuals with << bold >> and << shy >> behaviours. Behavioural profiles are different between the three groups of tortoises, the domestic group appeared to be bolder than the wild one. Moreover, for the wild group, bold individuals travel longer distances in the field, sometimes outside the protected areas. Thus, it is important to take into account the personality of individuals choosen for translocation projects.

ecology↗

bioRxiv2021

Global change affects differently at local scales animal populations: why Starlings still expands to the south while other temperate species go to the north?

Global change, which regroups global warming, landscape transformations and other anthropic modifications of ecosystems, has effects on populations and communities and produces modifications in the expansion area of species. While some species disappear, other ones are beneficiated by the new conditions and some of them evolve in new adapted forms or leave their ancient distribution area. As climate change tends to increase the temperature in several regions of the world, some species have been seen to leave areas in equatorial regions in order to join colder areas either towards the north of the northern hemisphere or towards the south of the southern one. Many birds as have moved geographically in direction to the poles and in many cases they have anticipated their laying dates. Actually, two tit species that use to lay their eggs in a period that their fledging dates synchronize with the emerging dates of caterpillars are now evolving to reproductive in periods earlier than before the climate change. Several species are reacting like that and other ones are moving to the north in Europe for example. Nevertheless, and very curiously, European starling, Sturnus vulgaris, populations are behaving on the contrary: their laying dates are moving towards later spring and their distribution area is moving towards the south. In this study we explore and discuss about different factors that may explain this difference from other birds.

ecology↗

bioRxiv2021

Population colonization history influences behavioral responses of European starlings in personality tests

To understand the processes involved in biological invasions, the genetic, morphological, physiological and behavioral characteristics of invasive populations need to be understood. Many invasive species have been reported to be flying species. In birds, both invaders and migrants encounter novel situations, therefore one could expect that both groups might react similarly to novelty. Here we analyzed the behavioral responses of individuals from three populations of European starling Sturnus vulgaris: a population settled for centuries in a rural region, a population that recently colonized an urban area, and a population of winter migrant birds. We conducted a social isolation test, a novel environment test, a novel food test and a novel object test to explore their reactions towards novelty. We identified and characterized different behavioral profiles for each test. The group of migratory adults appeared to be less anxious in social isolation than the group of urban young. Urban and migrant groups entered the novel environment sooner than rural birds. Shy, bold and intermediate individuals were observed in all three groups when presented with novel food. Finally, the proportion of shy individuals which did not touch the novel object was higher than the proportion of bold individuals in the rural group. Our study emphasizes that neophilia or boldness present in migrant and invasive populations may facilitate the occupation of novel habitats. Our analysis also suggests that mixed reactions of neophobia ensure behavioral flexibility in a gregarious invasive species. Significant statementIn this paper, we show that an invasive species like European starling, Sturnus vulgaris, presents an important flexibility in neophobia and in reaction towards social isolation. These variations depend on the settlement history of populationseven when the birds had been wild-caught as nestlings and hand-raised in standard conditions. This is significant because it highlights possible scenarios of colonization processes. We believe that this manuscript is appropriate for publication by Behavioral Ecology and Sociobiology because it places individuals behavior in the core mechanisms of an ecological phenomenom as biological invasions. Our manuscript enlarges the paradigms related to the ways of coping with novelty in animals. This manuscript has not been published and is not under consideration for publication elsewhere.

animal behavior and cognition↗

bioRxiv2021

Habituation, task solving and memorization may facilitate biological invasions: the Starling example

Invasions ecology deals more and more with behavioural characteristics of invasive species. Particularly, research have focused on the personality of invaders and on their way of coping with novelty in new habitats. Traits of neophobia may limit individuals in their exploration of novel objects or the consumption of novel foods, they may stop the access to valuable ressources. Actually, in novel environments like cities, food can be unreachable in throwaway dishes with lids or hidden in the garbage or even close to frightening objects. Animals may either left the place and waste these resources, or they can express low neophobia from the beginning and manipulate the objects to reach food. They may also habituate progressively to the context and use the ressources. Here we analyzed the behavioural responses of individuals from three populations of European starling Sturnus vulgaris: a population anciently settled in a rural region, a population that has recently colonized a urban area and a population of wintering migrant birds. We used a series of tests in order to explore if individuals would habituate to a novel object and if they could remember it eight months later. We explored if individuals would be less neophobic when confronted to two novel objects successively and we tested them in a learning task involving a novel object and an attractive food. Our results show that Sturnus vulgaris habituates rapidly to novel objects and that categorization facilitates neophobia lost when confronted to two different novel objects. Initially young birds appeared to be more skilled than adults in the learning task. Individuals from this species seem to be able to remember an object durably. We suggest that habituation, task solving and memorization are three mechanisms enhancing biological invasions.

animal behavior and cognition↗

bioRxiv2021

SOCIAL INFORMATION AND BIOLOGICAL INVASIONS: CHORUS SONGS ARE MORE ATTRACTIVE TO EUROPEAN STARLINGS IN MORE RECENTLY ESTABLISHED POPULATIONS.

When biological invasions by animals occur, the individuals arriving in novel environments can be confronted with unpredictable or unfamiliar resources and may need social interaction to improve survival in the newly colonized areas. Gathering with conspecifics and using social information about their activities may reveal the location of suitable feeding and breeding sites. This could compensate for the absence of individual information about new habitats and constitute an advantage for new settlers. If a tendency to gather in response to social stimuli is transmitted from one generation to the next, and if the benefit of gathering is lower in long time established populations, there should be behavioural differences in receptivity to social cues in populations with different colonizing histories. We hypothesized that individuals of a social species like the European starling from relatively recently-established populations would be more responsive to social cues than individuals belonging to long-established populations. We conducted playback experiments using a starling chorus to test its acoustic attractiveness to populations of starlings with different colonizing histories. We compared the reaction of individuals from two populations in rural Brittany, western France, established for a long time, with three more recently settled ones: two populations from a propagation front in southern Italy and one urban population from Rennes city in Brittany. Our data supported our hypothesis: individuals from more recent populations were more responsive to the acoustic stimulus, and gave more calls in flight than individuals from populations with an older settlement history. We discuss the different behavioural responses we observed in the different populations and the potential effects of habitat characteristics and starling densities.

animal behavior and cognition↗

bioRxiv2021

Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first-line treatment for CML, though approximately 40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to Imatinib. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and open-chromatin epigenetic mark, in CT22. Altogether our results suggest that large-scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated in a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.

cancer biology↗

bioRxiv2021

Artemisinin-based hybrids produce intracellular proteasome inhibitors that overcome resistance in Plasmodium falciparum

Artemisinin resistant Plasmodium falciparum (Pf) is spreading despite combination chemotherapy (ACT). Here we report the design of artezomibs, single-molecule hybrids of an artemisinin and a Pf-selective proteasome inhibitor. Artezomibs exert a novel mode of action inside the malaria parasites. The artemisinin component covalently modifies parasite proteins, which become substrates of the Pf proteasome. The proteasomal degradation products that bear the proteasome inhibitor component of the hybrid then inhibit Pf proteasomes, including those with mutations that reduce binding affinity of the proteasome inhibitor component on its own. We demonstrated that artezomibs circumvent both artemisinin resistance conferred by Kelch13 polymorphism and resistance to the proteasome inhibitor associated with mutations in Pf proteasomes. This mode of action may enable the use of a single molecule with one pharmacokinetic profile to prevent the emergence of resistance.

microbiology↗

bioRxiv2021

Targeting of Protein Kinase CK2 Elicits Antiviral Activity on Bovine Coronavirus Infection

Coronaviruses constitute a global threat to human population since three highly pathogenic coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) have crossed species to cause severe human respiratory disease. Considering the worldwide emergency status due to the current COVID-19 pandemic, effective pan-coronavirus antiviral drugs are required to tackle the ongoing as well as future (re)emerging virus outbreaks. Protein kinase CK2 has been deemed a promising therapeutic target in COVID-19 supported by its in vitro pharmacologic inhibition and molecular studies on SARS-CoV-2 infected cells. CIGB-325 is a first-in-class synthetic peptide impairing the CK2-mediated signaling whose safety and clinical benefit have been evidenced in Covid-19 and cancer patients after intravenous administration. Here, we explored the putative antiviral effect of CIGB-325 over MDBK cells infected by bovine coronavirus (BCoV) Mebus. Importantly, CIGB-325 inhibited both the cytopathic effect and the number of plaques forming units with a half-inhibitory concentrations IC50 = 3.5 M and 17.7 M, respectively. Accordingly, viral protein accumulation at the cytoplasm was clearly reduced by treating BCoV-infected cells with CIGB-325 over time, as determined by immunocytochemistry. Of note, data from pull-down assay followed by western blot and/or mass spectrometry identification revealed physical interaction of CIGB-325 with nucleocapsid (N) protein and a bona fide cellular CK2 substrates. Functional enrichment and network analysis from the CIGB-325 interacting proteins indicated cytoskeleton reorganization and protein folding as the most represented biological processes disturbed by this anti-CK2 peptide. Altogether, our findings not only unveil the direct antiviral activity of CIGB-325 on coronavirus infection but also provide molecular clues underlying such effect. Also, our data reinforce the scientific rationality behind the pharmacologic inhibition of CK2 to treat coronavirus infections.

pharmacology and toxicology↗

bioRxiv2021

Retinoic acid exerts sexually dimorphic effects over muscle energy metabolism and function

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and suppresses adiposity. Relative to WT, Rdh10+/- males experienced reduced fatty-acid oxidation, glucose intolerance and insulin resistance. Running endurance decreased 40%. Rdh10+/- females increased reliance on fatty acid oxidation and did not experience glucose intolerance nor insulin resistance. Running endurance improved 2.2-fold. Estrogen increased, revealed by a 40% increase in uterine weight. Because skeletal muscle energy use restricts adiposity and insulin resistance, we assessed the mixed fiber type gastrocnemius muscle (GM) to determine the effects of endogenous RA on muscle metabolism in vivo. RA in Rdh10+/- male GM decreased 38% relative to WT. TAG content increased 1.7-fold. Glut1 mRNA and glucose decreased >30%. Rdh10+/- male GM had impaired electron transport chain activity, and a 60% reduction in fasting ATP. The share of oxidative fibers increased, as did expression of the myogenic transcription factors Myog and Myf5. Centralized nuclei increased 5-fold in fibers--indicating muscle malady or repair. In Rdh10+/- female GM, RA decreased only 17%, due to a 1.8-fold increase in the estrogen-induced retinol dehydrogenase, Dhrs9. Rdh10+/- female GM did not amass TAG, increase oxidative fibers, decrease Glut1 mRNA or glucose, nor increase centralized nuclei. Expression of Myog and Myf5 decreased. Electron transport chain activity increased, elevating fasting ATP >3-fold. Thus, small decreases in skeletal muscle RA affect whole body energy use, insulin resistance and adiposity, in part through estrogen-related sexual dimorphic effects on mitochondria function.

biochemistry↗

bioRxiv2021

Effect of ozone exposure on Amyotrophic Lateral Sclerosis (ALS) pathology using a mice model of TDP-43 proteinopathy

BackgroundOzone (O3), one of the main photochemical pollutants in the atmosphere today, is a serious health risk factor. Although the effects of O3 exposure have been documented on many diseases, they have not yet been examined on Amyotrophic Lateral Sclerosis (ALS)- a fatal progressive and neurodegenerative disease. ObjectivesTo investigate the effect of the O3 exposure in a mice model of TDP-43 proteinopathy, exploring a possible association between the O3 exposure and the ALS pathogenesis. MethodsTDP-43A315T and wild-type (WT) mice were exposed to O3 (0.25 ppm) or filtered air (FA) for 15 days (4 hours/day). We assessed (1) weight loss (2) motor performance (3) plasma glucose content and (4) metabolic markers from plasma samples of the animals. ResultsThroughout the experiment, we observed a progressive decline in body weight and the motor coordination in TDP-43A315T mice compared to WT controls. Although there was a trend, there were no significant differences in the decline of body weight of TDP-43A315T mice when exposed to either FA or O3. In O3-TDP-43A315T mice, the disease duration lasted longer. In addition, O3-TDP-43A315T mice showed improvements in motor performance as well TDP-43A315T mice were hypoglycemic compared to WT mice. However, FA-TDP-43A315T mice showed lower plasma glucose levels at the disease end-stage. We found altered levels of adipokines and metabolic proteins in TDP-43A315T mice compared to WT controls. A positive correlation was found among GIP and glucagon compared to insulin concentrations in control mice. Interestingly, resistin, Gastric Inhibitory Peptide (GIP), Glucagon Like Peptide 1 (GIP-1) and insulin levels were higher in O3-TDP-43A315T mice. DiscussionWe provide new evidence about a mechanistic link between O3 exposure and the improvement of the metabolic disturbances present in TDP-43A315T mice. Further studies are needed to corroborate the obtained results as they warrant to understanding the underlying mechanisms.

neuroscience↗

bioRxiv2020

MaPPeRTrac: A Massively Parallel, Portable, and Reproducible Tractography Pipeline

Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational cost. We developed MaPPeRTrac, a probabilistic tractography pipeline that simplifies and vastly accelerates this process on a wide range of high performance computing (HPC) environments. It fully automates the entire tractography pipeline, from management of raw MRI machine data to edge density imaging (EDI) of the structural connectome. Dependencies are containerized with Docker or Singularity and de-coupled from code to enable rapid proto-typing and modification. Data artifacts are strictly organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming frame-work, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so that it may accelerate brain connectome research for a broader user community.

neuroscience↗

bioRxiv2020

Empty sella syndrome as a window into the neuroprotective effects of prolactin

BACKGROUNDTo correlate structural integrity of visual pathway white matter tracts with prolactin levels in a patient who demonstrates downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma. METHODSA 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects nine years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over one year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point. RESULTSShortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p<0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time. CONCLUSIONSThese results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of diffusion and visual function provide support for a neuroprotective role of prolactin in the injured nervous system.

neuroscience↗

bioRxiv2020

MiniFAST: A sensitive and fast miniaturized microscope for in vivo neural recording

Observing the activity of large populations of neurons in vivo is critical for understanding brain function and dysfunction. The use of fluorescent genetically-encoded calcium indicators (GECIs) in conjunction with miniaturized microscopes is an exciting emerging toolset for recording neural activity in unrestrained animals. Despite their potential, current miniaturized microscope designs are limited by using image sensors with low frame rates, sensitivity, and resolution. Beyond GECIs, there are many neuroscience applications which would benefit from the use of other emerging neural indicators, such as fluorescent genetically-encoded voltage indicators (GEVIs) that have faster temporal resolution to match neuron spiking, yet, require imaging at high speeds to properly sample the activity-dependent signals. We integrated an advanced CMOS image sensor into a popular open-source miniaturized microscope platform. MiniFAST is a fast and sensitive miniaturized microscope capable of 1080p video (1920x1080 pixels), 1.5 {micro}m resolution, frame rates up to 500 Hz (achieved with windowing: 1920 x 55 pixels height) and high gain ability (up to 70 dB) to image in extremely low light conditions. We report results of [~]300 Hz in vivo imaging of freely behaving transgenic Thy1-GCaMP6f mice, high speed 500 Hz in vitro imaging of a GEVI and in vivo GEVI imaging in head-fixed mice. Our results extend miniaturized microscope capabilities in high-speed imaging, high sensitivity and increased resolution, opening the door for the open-source community to use fast and dim neural indicators.

neuroscience↗