Publications by authors named "Alexander Maier"

124 Publications

Identification of seven psychedelic 2,5-dimethoxy-phenylethyl-amine-based designer drugs via benchtop H nuclear magnetic resonance spectroscopy.

Magn Reson Chem 2021 Aug 17. Epub 2021 Aug 17.

Application Chemistry, Nanalysis Corp., Calgary, Alberta, Canada.

The dissemination of spectral information of new psychoactive substances (NPS) acquired on benchtop nuclear magnetic resonance (NMR) spectrometers is of high importance considering the emerging application of such portable and accessible instruments in forensic analyses. Seven members of the 2C-X series (2C-B, 2C-C, 2C-D, 2C-E, 2C-P, 2C-T2, and 2C-T7) of NPS were analyzed via 60 MHz H benchtop NMR spectroscopy and their molecular structural relations are discussed with respect to the observed proton NMR spectra.
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http://dx.doi.org/10.1002/mrc.5205DOI Listing
August 2021

Pulmonary Artery F-Fluorodeoxyglucose Uptake by PET/CMR as a Marker of Pulmonary Hypertension in Sarcoidosis.

JACC Cardiovasc Imaging 2021 Jul 8. Epub 2021 Jul 8.

BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Objectives: This study investigated whether pulmonary artery (PA) F-FDG uptake is associated with hypertension, and if it correlates to elevated pulmonary pressures.

Background: F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography or cardiac magnetic resonance (CMR) has been used to assess inflammation mostly in large arteries of the systemic circulation. Much less is known about inflammation of the vasculature of the pulmonary system and its relationship to pulmonary hypertension (PH).

Methods: In a single-center cohort of 175 patients with suspected cardiac sarcoidosis, who underwent hybrid thoracic PET/CMR, F-FDG uptake in the PA was quantified according to maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) and compared with available results from right heart catheterization (RHC) or transthoracic echocardiography (TTE).

Results: Thirty-three subjects demonstrated clear F-FDG uptake in the PA wall. In the subgroup of patients who underwent RHC (n = 10), the mean PA pressure was significantly higher in the group with PA F-FDG uptake compared with the group without uptake (34.4 ± 7.2 mm Hg vs 25.6 ± 9.3 mm Hg; P = 0.003), and 9 (90%) patients with PA F-FDG uptake had PH when a mean PA pressure cutoff of 25 mm Hg was used compared with 18 (45%) in the nonuptake group (P < 0.05). In the subgroup that underwent TTE, signs of PH were present in a significantly higher number of patients with PA F-FDG uptake (14 [51.9%] vs 37 [29.8%]; P < 0.05). Qualitative assessment of F-FDG uptake in the PA wall showed a sensitivity of 33% and specificity of 96% for separating patients with PH based on RHC-derived PA pressures. SUVmax and TBR in the PA wall correlated with PA pressure derived from RHC and/or TTE.

Conclusions: We demonstrate that F-FDG uptake by PET/CMR in the PA is associated with PH and that its intensity correlates with PA pressure.
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http://dx.doi.org/10.1016/j.jcmg.2021.05.023DOI Listing
July 2021

Sex-specific Separation of Gametocyte Populations.

Bio Protoc 2021 Jun 5;11(11):e4045. Epub 2021 Jun 5.

Research School of Biology, The Australian National University, Canberra ACT 2601, Australia.

is a unicellular eukaryotic parasite that causes malaria in humans. The parasite is spread by mosquitoes after ingestion of sexual stage parasites known as gametocytes. Malaria transmission depends on parasites switching from the disease-causing asexual blood forms to male and female gametocytes. The current protocol allows the simultaneous isolation of male and female parasites from the same population to study this critical lifecycle stage in a sex-specific manner. We have generated a transgenic cell line that expresses a GFP-tagged parasite protein in female, but not male, parasites. Gametocyte production is stress induced and, through a series of steps, sexual stage parasites are enriched relative to uninfected red blood cells or red blood cells infected with asexual stage parasites. Finally, male and female gametocytes are separated by fluorescence-activated cell sorting. This protocol allows for the separation of up to 12 million live male and female parasites from the same population, which are amenable to further analysis.
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http://dx.doi.org/10.21769/BioProtoc.4045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249911PMC
June 2021

Risk factors and protective factors of depression in older people 65+. A systematic review.

PLoS One 2021 13;16(5):e0251326. Epub 2021 May 13.

Faculty of Medicine, Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.

Objectives: Identifying risk factors of depression can provide a better understanding of the disorder in older people. However, to minimize bias due to the influence of confounders and to detect reverse influence, a focus on longitudinal studies using multivariate analysis is required.

Design: A systematic literature search was conducted by searching the databases MEDLINE, Cochrane, PsycINFO and Web of Science for all relevant articles published from January 2000 to the end of March 2020. The following inclusion criteria were used: prospective design, nationally or regionally representative sample, published in English or German, analyzed risk factors for depression of individuals 65+ identified by multivariate analysis, and provided validity of diagnostic instrument. All results of multivariate analysis were reported and summarized.

Results: Thirty articles were identified. Heterogeneous results were found for education, female gender, self-rated health, cognitive impairment and older age, although significant in several studies. Findings hinted at a protective quality of physical activity. In terms of physical health, chronic disease and difficulty initiating sleep homogeneously increased risk of depression. Mobility impairment resulted as a risk factor in three studies. IADL impairment and vision impairment were mostly identified as significant risk factors. Alcohol consumption and smoking behavior yielded heterogenous results. Psychosocial factors were assessed similarly in multiple studies and yielded heterogenous results.

Limitations: Research was limited to articles published in English or German. Length of follow up was not considered for the presentation of results. Adjustments for and inclusion of different variables in the studies may distort results.

Conclusion: Our findings demonstrate the necessity of refined, more comparable assessment tools for evaluating potential risk factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118343PMC
May 2021

Of membranes and malaria: phospholipid asymmetry in Plasmodium falciparum-infected red blood cells.

Cell Mol Life Sci 2021 May 13;78(10):4545-4561. Epub 2021 Mar 13.

Research School of Biology, The Australian National University, Canberra, Australia.

Malaria is a vector-borne parasitic disease with a vast impact on human history, and according to the World Health Organisation, Plasmodium parasites still infect over 200 million people per year. Plasmodium falciparum, the deadliest parasite species, has a remarkable ability to undermine the host immune system and cause life-threatening disease during blood infection. The parasite's host cells, red blood cells (RBCs), generally maintain an asymmetric distribution of phospholipids in the two leaflets of the plasma membrane bilayer. Alterations to this asymmetry, particularly the exposure of phosphatidylserine (PS) in the outer leaflet, can be recognised by phagocytes. Because of the importance of innate immune defence numerous studies have investigated PS exposure in RBCs infected with P. falciparum, but have reached different conclusions. Here we review recent advancements in our understanding of the molecular mechanisms which regulate asymmetry in RBCs, and whether infection with the P. falciparum parasite results in changes to PS exposure. On the balance of evidence, it is likely that membrane asymmetry is disrupted in parasitised RBCs, though some methodological issues need addressing. We discuss the potential causes and consequences of altered asymmetry in parasitised RBCs, particularly for in vivo interactions with the immune system, and the role of host-parasite co-evolution. We also examine the potential asymmetric state of parasite membranes and summarise current knowledge on the parasite proteins, which could regulate asymmetry in these membranes. Finally, we highlight unresolved questions at this time and the need for interdisciplinary approaches to uncover the machinery which enables P. falciparum parasites to hide in mature erythrocytes.
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http://dx.doi.org/10.1007/s00018-021-03799-6DOI Listing
May 2021

Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells.

PLoS Pathog 2021 02 18;17(2):e1009259. Epub 2021 Feb 18.

Research School of Biology, The Australian National University, Canberra, Australia.

The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.
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http://dx.doi.org/10.1371/journal.ppat.1009259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891792PMC
February 2021

Binocular Suppression in the Macaque Lateral Geniculate Nucleus Reveals Early Competitive Interactions between the Eyes.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 8.

Department of Psychology, College of Arts and Science, Vanderbilt Vision Research Center, Center for Integrative and Cognitive Neuroscience, Vanderbilt University, Nashville, TN 37235.

The lateral geniculate nucleus (LGN) of the dorsal thalamus is the primary recipient of the two eyes' outputs. Most LGN neurons are monocular in that they are activated by visual stimulation through only one (dominant) eye. However, there are both intrinsic connections and inputs from binocular structures to the LGN that could provide these neurons with signals originating from the other (non-dominant) eye. Indeed, previous work introducing luminance differences across the eyes or using a single-contrast stimulus showed binocular modulation for single unit activity in anesthetized macaques and multiunit activity in awake macaques. Here, we sought to determine the influence of contrast viewed by both the non-dominant and dominant eyes on LGN single-unit responses in awake macaques. To do this, we adjusted each eye's signal strength by independently varying the contrast of stimuli presented to the two eyes. Specifically, we recorded LGN single unit spiking activity in two awake macaques while they viewed drifting gratings of varying contrast. We found that LGN neurons of all types [parvocellular (P), magnocellular (M), and koniocellular (K)] were significantly suppressed when stimuli were presented at low contrast to the dominant eye and at high contrast to the non-dominant eye. Further, the inputs of the two eyes showed antagonistic interaction, whereby the magnitude of binocular suppression diminished with high contrast in the dominant eye, or low contrast in the non-dominant eye. These results suggest that the LGN represents a site of precortical binocular processing involved in resolving discrepant contrast differences between the eyes.
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http://dx.doi.org/10.1523/ENEURO.0364-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035044PMC
June 2021

Stimulus Feature-Specific Information Flow Along the Columnar Cortical Microcircuit Revealed by Multivariate Laminar Spiking Analysis.

Front Syst Neurosci 2020 30;14:600601. Epub 2020 Nov 30.

Department of Psychology, Vanderbilt University, Nashville, TN, United States.

Most of the mammalian neocortex is comprised of a highly similar anatomical structure, consisting of a granular cell layer between superficial and deep layers. Even so, different cortical areas process different information. Taken together, this suggests that cortex features a canonical functional microcircuit that supports region-specific information processing. For example, the primate primary visual cortex (V1) combines the two eyes' signals, extracts stimulus orientation, and integrates contextual information such as visual stimulation history. These processes co-occur during the same laminar stimulation sequence that is triggered by the onset of visual stimuli. Yet, we still know little regarding the laminar processing differences that are specific to each of these types of stimulus information. Univariate analysis techniques have provided great insight by examining one electrode at a time or by studying average responses across multiple electrodes. Here we focus on multivariate statistics to examine response patterns across electrodes instead. Specifically, we applied multivariate pattern analysis (MVPA) to linear multielectrode array recordings of laminar spiking responses to decode information regarding the eye-of-origin, stimulus orientation, and stimulus repetition. MVPA differs from conventional univariate approaches in that it examines patterns of neural activity across simultaneously recorded electrode sites. We were curious whether this added dimensionality could reveal neural processes on the population level that are challenging to detect when measuring brain activity without the context of neighboring recording sites. We found that eye-of-origin information was decodable for the entire duration of stimulus presentation, but diminished in the deepest layers of V1. Conversely, orientation information was transient and equally pronounced along all layers. More importantly, using time-resolved MVPA, we were able to evaluate laminar response properties beyond those yielded by univariate analyses. Specifically, we performed a time generalization analysis by training a classifier at one point of the neural response and testing its performance throughout the remaining period of stimulation. Using this technique, we demonstrate repeating (reverberating) patterns of neural activity that have not previously been observed using standard univariate approaches.
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http://dx.doi.org/10.3389/fnsys.2020.600601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734135PMC
November 2020

Theta, but Not Gamma Oscillations in Area V4 Depend on Input from Primary Visual Cortex.

Curr Biol 2021 02 4;31(3):635-642.e3. Epub 2020 Dec 4.

Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Neuroscience and Movement Science, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 5, 1700 Fribourg, Switzerland. Electronic address:

Theta (3-9 Hz) and gamma (30-100 Hz) oscillations have been observed at different levels along the hierarchy of cortical areas and across a wide set of cognitive tasks. In the visual system, the emergence of both rhythms in primary visual cortex (V1) and mid-level cortical areas V4 has been linked with variations in perceptual reaction times. Based on analytical methods to infer causality in neural activation patterns, it was concluded that gamma and theta oscillations might both reflect feedforward sensory processing from V1 to V4. Here, we report on experiments in macaque monkeys in which we experimentally assessed the presence of both oscillations in the neural activity recorded from multi-electrode arrays in V1 and V4 before and after a permanent V1 lesion. With intact cortex, theta and gamma oscillations could be reliably elicited in V1 and V4 when monkeys viewed a visual contour illusion and showed phase-to-amplitude coupling. Laminar analysis in V1 revealed that both theta and gamma oscillations occurred primarily in the supragranular layers, the cortical output compartment of V1. However, there was a clear dissociation between the two rhythms in V4 that became apparent when the major feedforward input to V4 was removed by lesioning V1: although V1 lesioning eliminated V4 theta, it had little effect on V4 gamma power except for delaying its emergence by >100 ms. These findings suggest that theta is more tightly associated with feedforward processing than gamma and pose limits on the proposed role of gamma as a feedforward mechanism.
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http://dx.doi.org/10.1016/j.cub.2020.10.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018535PMC
February 2021

Multimodal imaging of bacterial-host interface in mice and piglets with endocarditis.

Sci Transl Med 2020 11;12(568)

Green Mountain Antibodies, Burlington, VT 05401, USA.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill that colonizes the heart's valves. relies on virulence factors to evade therapeutics and the host's immune response, usurping the host's clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.
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http://dx.doi.org/10.1126/scitranslmed.aay2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818516PMC
November 2020

Growing evidence for separate neural mechanisms for attention and consciousness.

Atten Percept Psychophys 2021 Feb 9;83(2):558-576. Epub 2020 Oct 9.

Turner Institute for Brain and Mental Health & School of Psychological Sciences, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Melbourne, VIC, Australia.

Our conscious experience of the world seems to go in lockstep with our attentional focus: We tend to see, hear, taste, and feel what we attend to, and vice versa. This tight coupling between attention and consciousness has given rise to the idea that these two phenomena are indivisible. In the late 1950s, the honoree of this special issue, Charles Eriksen, was among a small group of early pioneers that sought to investigate whether a transient increase in overall level of attention (alertness) in response to a noxious stimulus can be decoupled from conscious perception using experimental techniques. Recent years saw a similar debate regarding whether attention and consciousness are two dissociable processes. Initial evidence that attention and consciousness are two separate processes primarily rested on behavioral data. However, the past couple of years witnessed an explosion of studies aimed at testing this conjecture using neuroscientific techniques. Here we provide an overview of these and related empirical studies on the distinction between the neuronal correlates of attention and consciousness, and detail how advancements in theory and technology can bring about a more detailed understanding of the two. We argue that the most promising approach will combine ever-evolving neurophysiological and interventionist tools with quantitative, empirically testable theories of consciousness that are grounded in a mathematically formalized understanding of phenomenology.
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http://dx.doi.org/10.3758/s13414-020-02146-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886945PMC
February 2021

An apicoplast-resident folate transporter is essential for sporogony of malaria parasites.

Cell Microbiol 2021 01 8;23(1):e13266. Epub 2020 Oct 8.

Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.

Malaria parasites are fast replicating unicellular organisms and require substantial amounts of folate for DNA synthesis. Despite the central role of this critical co-factor for parasite survival, only little is known about intraparasitic folate trafficking in Plasmodium. Here, we report on the expression, subcellular localisation and function of the parasite's folate transporter 2 (FT2) during life cycle progression in the murine malaria parasite Plasmodium berghei. Using live fluorescence microscopy of genetically engineered parasites, we demonstrate that FT2 localises to the apicoplast. In invasive P. berghei stages, a fraction of FT2 is also observed at the apical end. Upon genetic disruption of FT2, blood and liver infection, gametocyte production and mosquito colonisation remain unaltered. But in the Anopheles vector, FT2-deficient parasites develop inflated oocysts with unusual pulp formation consisting of numerous single-membrane vesicles, which ultimately fuse to form large cavities. Ultrastructural analysis suggests that this defect reflects aberrant sporoblast formation caused by abnormal vesicular traffic. Complete sporogony in FT2-deficient oocysts is very rare, and mutant sporozoites fail to establish hepatocyte infection, resulting in a complete block of parasite transmission. Our findings reveal a previously unrecognised organellar folate transporter that exerts critical roles for pathogen maturation in the arthropod vector.
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http://dx.doi.org/10.1111/cmi.13266DOI Listing
January 2021

Novel Method for the Separation of Male and Female Gametocytes of the Malaria Parasite That Enables Biological and Drug Discovery.

mSphere 2020 08 12;5(4). Epub 2020 Aug 12.

Research School of Biology, The Australian National University, Canberra, Australia

We developed a flow-cytometry-based method to separate and collect cocultured male and female gametocytes responsible for malaria transmission. The purity of the collected cells was estimated at >97% using flow cytometry, and sorted cells were observed by Giemsa-stained thin-smear and live-cell fluorescence microscopy. The expression of validated sex-specific markers corroborated the sorting strategy. Collected male and female gametocytes were used to confirm three novel sex-specific markers by quantitative real-time PCR that were more enriched in sorted male and female gametocyte populations than existing sex-specific markers. We also applied the method as a proof-of-principle drug screen that allows the identification of drugs that kill gametocytes in a sex-specific manner. Since the developed method allowed for the separation of male and female parasites from the same culture, we observed for the first time a difference in development time between the sexes: females developed faster than males. Hence, the ability to separate male and female gametocytes opens the door to a new field of sex-specific gametocyte biology to further our understanding of malaria transmission. The protozoan causes the most severe form of human malaria. The development of sexual forms (so-called gametocytes) is crucial for disease transmission. However, knowledge of these forms is severely hampered by the paucity of sex-specific markers and the inability to extract single sex gametocytes in high purity. Moreover, the identification of compounds that specifically affect one sex is difficult due to the female bias of the gametocytes. We have developed a system that allows for the separation of male and female gametocytes from the same population. Applying our system, we show that male and female parasites mature at different rates, which might have implications for transmission. We also identified new sex-specific genes that can be used as sex markers or to unravel sex-specific functions. Our system will not only aid in the discovery of much needed gametocidal compounds, but it also represents a valuable tool for exploring malaria transmission biology.
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http://dx.doi.org/10.1128/mSphere.00671-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426174PMC
August 2020

Visual Perception: Human Brain Cells Cause a Change of View.

Authors:
Alexander Maier

Curr Biol 2020 08;30(16):R939-R941

Department of Psychology, Department of Ophthalmology and Visual Sciences, Vanderbilt Vision Research Center, Center for Integrative and Cognitive Neuroscience, Vanderbilt Brain Institute, Vanderbilt University, Wilson Hall, 111 21(st) Avenue South, Nashville, TN 37325, USA. Electronic address:

Some images spontaneously change in appearance. A new study has found that these changes are reflected in high-level visual cortical areas before they become apparent in early sensory cortex. This suggests that visual information not only flows towards interpretative areas of our brain, but also in the reverse direction.
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http://dx.doi.org/10.1016/j.cub.2020.06.054DOI Listing
August 2020

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

Sci Rep 2020 08 6;10(1):13211. Epub 2020 Aug 6.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.
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http://dx.doi.org/10.1038/s41598-020-70043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413393PMC
August 2020

Distinct adaptations of a gametocyte ABC transporter to murine and human Plasmodium parasites and its incompatibility in cross-species complementation.

Int J Parasitol 2020 06 21;50(6-7):511-522. Epub 2020 May 21.

Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. Electronic address:

Parasites of the genus Plasmodium infect a wide range of mammalian hosts including humans, primates, bats and arboreal rodents. A hallmark of Plasmodium spp. is the very narrow host range, indicative of matching parasite-host coevolution. Accordingly, their respective genomes harbour many unique genes and gene families that typically encode proteins involved in host cell recognition and remodelling. Whether and to what extent conserved proteins that are shared across Plasmodium spp. also exert distinct species-specific roles remains largely untested. Here, we present detailed functional profiling of the female gametocyte-specific ATP-binding cassette transporter gABCG2 in the murine parasite Plasmodium berghei and compare our findings with data from the orthologous gene in the human parasite Plasmodium falciparum. We show that P. berghei gABCG2 is female-specific and continues to be expressed in zygotes and ookinetes. In contrast to a distinct localization to Iipid-rich gametocyte-specific spots as observed in P. falciparum, the murine malaria parasite homolog is found at the parasite plasma membrane. Plasmodium berghei lacking gABCG2 displays fast asexual blood-stage replication and increased proportions of female gametocytes, consistent with the corresponding P. falciparum knock-out phenotype. Strikingly, cross-species replacement of gABCG2 in either the murine or the human parasite did not restore normal growth rates. The lack of successful complementation despite high conservation across Plasmodium spp. is an indicator of distinct adaptations and tight parasite-host coevolution. Hence, incompatibility of conserved genes in closely related Plasmodium spp. might be more common than previously anticipated.
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http://dx.doi.org/10.1016/j.ijpara.2020.03.009DOI Listing
June 2020

Perceptual rivalry across animal species.

J Comp Neurol 2020 12 1;528(17):3123-3133. Epub 2020 Jun 1.

Department of Psychology, Vanderbilt University, Nashville, Tennessee, USA.

This review in memoriam of Jack Pettigrew provides an overview of past and current research into the phenomenon of multistable perception across multiple animal species. Multistable perception is characterized by two or more perceptual interpretations spontaneously alternating, or rivaling, when animals are exposed to stimuli with inherent sensory ambiguity. There is a wide array of ambiguous stimuli across sensory modalities, ranging from the configural changes observed in simple line drawings, such as the famous Necker cube, to the alternating perception of entire visual scenes that can be instigated by interocular conflict. The latter phenomenon, called binocular rivalry, in particular caught the attention of the late Jack Pettigrew, who combined his interest in the neuronal basis of perception with a unique comparative biological approach that considered ambiguous sensation as a fundamental problem of sensory systems that has shaped the brain throughout evolution. Here, we examine the research findings on visual perceptual alternation and suppression in a wide variety of species including insects, fish, reptiles, and primates. We highlight several interesting commonalities across species and behavioral indicators of perceptual alternation. In addition, we show how the comparative approach provides new avenues for understanding how the brain suppresses opposing sensory signals and generates alternations in perceptual dominance.
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http://dx.doi.org/10.1002/cne.24939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541519PMC
December 2020

Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging.

Nat Nanotechnol 2020 05 20;15(5):398-405. Epub 2020 Apr 20.

BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ischaemic heart disease evokes a complex immune response. However, tools to track the systemic behaviour and dynamics of leukocytes non-invasively in vivo are lacking. Here, we present a multimodal hot-spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (F-HDL) to allow myeloid cell tracking by F magnetic resonance imaging. The F-HDL nanotracer can additionally be labelled with zirconium-89 and fluorophores to detect myeloid cells by in vivo positron emission tomography imaging and optical modalities, respectively. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo F-HDL magnetic resonance imaging. Concurrently, using ex vivo techniques, we showed that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and at the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox, enabling the study of complex myeloid cell behaviour dynamically.
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http://dx.doi.org/10.1038/s41565-020-0642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416336PMC
May 2020

Priming of Attentional Selection in Macaque Visual Cortex: Feature-Based Facilitation and Location-Based Inhibition of Return.

eNeuro 2020 Mar/Apr;7(2). Epub 2020 Apr 24.

Department of Psychology, Center for Integrative and Cognitive Neuroscience, Vanderbilt Vision Research Center, College of Arts and Sciences, Vanderbilt University, Nashville, Tennessee 37240

Visual search performance varies with stimulus and response history. Priming of pop-out refers to increased accuracy and reduced response time with repeated presentation of particular singleton and distractor features (e.g., a red target among green distractor stimuli), which are abruptly impaired when singleton and distractor features swap (e.g., green target among red distractors). Meanwhile, inhibition of return refers to the slowing of response time when target location repeats. Neurophysiological correlates of both these phenomena have been reported in the frontal eye field (FEF), an area in the frontal lobe contributing to attentional selection and eye movement planning. To understand the mechanistic origin of these adaptive behaviors, we investigated visual cortical area V4, an area providing input to and receiving feedback from FEF, during feature-based priming of pop-out and location-based inhibition of return. Performing a color pop-out task, monkeys exhibited pronounced priming of pop-out and inhibition of return. Neural spiking from V4 revealed earlier target selection associated with priming of pop-out and delayed selection associated with inhibition of return. These results demonstrate substantial involvement of extrastriate visual cortex in behavioral priming and inhibition of return.
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http://dx.doi.org/10.1523/ENEURO.0466-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189490PMC
June 2021

-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis.

Elife 2020 02 18;9. Epub 2020 Feb 18.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for - and -IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.
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http://dx.doi.org/10.7554/eLife.51546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048393PMC
February 2020

A logistic regression analysis comparing minimalistic approach and intubation anaesthesia in patients undergoing transfemoral transcatheter aortic valve replacement.

PLoS One 2020 5;15(2):e0227345. Epub 2020 Feb 5.

Department of Cardiology and Angiology I, Faculty of Medicine, Heart Centre Freiburg University, University of Freiburg, Freiburg, Germany.

Aims: Patients with postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR) are ventilated and hospitalized longer and suffer increased in-hospital mortality. This study hypothesized that a minimalistic approach with conscious sedation during transfemoral aortic valve replacement (TF-AVR) protects against delirium, time of mechanical ventilation, and increased length of stay in intensive care unit (ICU) compared to intubation anaesthesia.

Methods And Results: 308 patients which underwent TF-AVR in our centre between 01/2013 and 08/2017 were retrospectively evaluated regarding postoperative delirium, time of mechanical ventilation, and days in ICU. TF-AVR was performed with intubation anaesthesia in 245 patients and with conscious sedation in 63. The operative risk estimated by the logEUROScore was similar in both groups (intubation: 13.28 +/-9.06%, conscious sedation: 12.24 +/-6.77%, p = 0.395). In the conscious sedation group procedure duration was shorter (0.61 +/-0.91h vs. 1.75 +/-0.96h, p<0.001). The risk for intraprocedural complications was not influenced by the anaesthesia method (OR conscious sedation instead of intubation 1.66, p = 0.117), but days on ICU (-2.21 days, p<0.0001) and minutes of mechanical ventilation (-531.2 min, p < 0.0001) were reduced. Furthermore, the risk of POD was decreased when TF-AVR was performed under conscious sedation (6.35% vs. 18.18%, OR 0.29, p = 0.021).

Conclusions: Time of mechanical ventilation, risk of POD, and days on ICU were substantially reduced in patients who underwent TF-AVR under conscious sedation. Our data suggest that TF-AVR with conscious sedation is safe with a beneficial postoperative course in clinical practice, and should be considered the favoured approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001937PMC
April 2020

Performance Monitoring during Visual Priming.

J Cogn Neurosci 2020 03 4;32(3):515-526. Epub 2019 Nov 4.

Vanderbilt University.

Repetitive performance of single-feature (efficient or pop-out) visual search improves RTs and accuracy. This phenomenon, known as priming of pop-out, has been demonstrated in both humans and macaque monkeys. We investigated the relationship between performance monitoring and priming of pop-out. Neuronal activity in the supplementary eye field (SEF) contributes to performance monitoring and to the generation of performance monitoring signals in the EEG. To determine whether priming depends on performance monitoring, we investigated spiking activity in SEF as well as the concurrent EEG of two monkeys performing a priming of pop-out task. We found that SEF spiking did not modulate with priming. Surprisingly, concurrent EEG did covary with priming. Together, these results suggest that performance monitoring contributes to priming of pop-out. However, this performance monitoring seems not mediated by SEF. This dissociation suggests that EEG indices of performance monitoring arise from multiple, functionally distinct neural generators.
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http://dx.doi.org/10.1162/jocn_a_01499DOI Listing
March 2020

Temporal dynamics of binocular integration in primary visual cortex.

J Vis 2019 10;19(12):13

Department of Psychology, College of Arts and Science, Vanderbilt Vision Research Center, Center for Cognitive and Integrative Neuroscience, Vanderbilt University, Nashville, TN, USA.

Whenever we open our eyes, our brain quickly integrates the two eyes' perspectives into a combined view. This process of binocular integration happens so rapidly that even incompatible stimuli are briefly fused before one eye's view is suppressed in favor of the other (binocular rivalry). The neuronal basis for this brief period of fusion during incompatible binocular stimulation is unclear. Neuroanatomically, the eyes provide two largely separate streams of information that are integrated into a binocular response by the primary visual cortex (V1). However, the temporal dynamics underlying the formation of this binocular response are largely unknown. To address this question, we examined the temporal profile of binocular responses in V1 of fixating monkeys. We found that V1 processes binocular stimuli in a dynamic sequence that comprises at least two distinct temporal phases. An initial transient phase is characterized by enhanced spiking responses for both compatible and incompatible binocular stimuli compared to monocular stimulation. This transient is followed by a sustained response that differed markedly between congruent and incongruent binocular stimulation. Specifically, incompatible binocular stimulation resulted in overall response reduction relative to monocular stimulation (binocular suppression). In contrast, responses to compatible stimuli were either suppressed or enhanced (binocular facilitation) depending on the neurons' ocularity (selectivity for one eye over the other) and laminar location. These results suggest that binocular integration in V1 occurs in at least two sequential steps that comprise initial additive combination of the two eyes' signals followed by widespread differentiation between binocular concordance and discordance.
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http://dx.doi.org/10.1167/19.12.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797477PMC
October 2019

An iterative sparse deconvolution method for simultaneous multicolor F-MRI of multiple contrast agents.

Magn Reson Med 2020 01 23;83(1):228-239. Epub 2019 Aug 23.

Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: F-MRI is gaining widespread interest for cell tracking and quantification of immune and inflammatory cells in vivo. Different fluorinated compounds can be discriminated based on their characteristic MR spectra, allowing in vivo imaging of multiple F compounds simultaneously, so-called multicolor F-MRI. We introduce a method for multicolor F-MRI using an iterative sparse deconvolution method to separate different F compounds and remove chemical shift artifacts arising from multiple resonances.

Methods: The method employs cycling of the readout gradient direction to alternate the spatial orientation of the off-resonance chemical shift artifacts, which are subsequently removed by iterative sparse deconvolution. Noise robustness and separation was investigated by numerical simulations. Mixtures of fluorinated oils (PFCE and PFOB) were measured on a 7T MR scanner to identify the relation between F signal intensity and compound concentration. The method was validated in a mouse model after intramuscular injection of fluorine probes, as well as after intravascular injection.

Results: Numerical simulations show efficient separation of F compounds, even at low signal-to-noise ratio. Reliable chemical shift artifact removal and separation of PFCE and PFOB signals was achieved in phantoms and in vivo. Signal intensities correlated excellently to the relative F compound concentrations (r = 0.966/0.990 for PFOB/PFCE).

Conclusions: The method requires minimal sequence adaptation and is therefore easily implemented on different MRI systems. Simulations, phantom experiments, and in-vivo measurements in mice showed effective separation and removal of chemical shift artifacts below noise level. We foresee applicability for simultaneous in-vivo imaging of F-containing fluorine probes or for detection of F-labeled cell populations.
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http://dx.doi.org/10.1002/mrm.27926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852267PMC
January 2020

Figure-Ground Modulation in the Human Lateral Geniculate Nucleus Is Distinguishable from Top-Down Attention.

Curr Biol 2019 06 6;29(12):2051-2057.e3. Epub 2019 Jun 6.

Department of Psychology, Vanderbilt University, Nashville, TN 37240, USA; Vanderbilt Vision Research Center, Vanderbilt University, Nashville, TN 37240, USA.

Nearly all of the information that reaches the primary visual cortex (V1) of the brain passes from the retina through the lateral geniculate nucleus (LGN) of the thalamus. Although the LGN's role in relaying feedforward signals from the retina to the cortex is well understood [1, 2], the functional role of the extensive feedback it receives from the cortex has remained elusive [3-6]. Here, we investigated whether corticothalamic feedback may contribute to perceptual processing in the LGN in a manner that is distinct from top-down effects of attention [7-10]. We used high-resolution fMRI at 7 Tesla to simultaneously measure responses to orientation-defined figures in the human LGN and V1. We found robust enhancement of perceptual figures throughout the early visual system, which could be distinguished from the effects of covert spatial attention [11-13]. In a second experiment, we demonstrated that figure enhancement occurred in the LGN even when the figure and surrounding background were presented dichoptically (i.e., to different eyes). As binocular integration primarily occurs in V1 [14, 15], these results implicate a mechanism of automatic, contextually sensitive feedback from binocular visual cortex underlying figure-ground modulation in the LGN. Our findings elucidate the functional mechanisms of this core function of the visual system [16-18], which allows people to segment and detect meaningful figures in complex visual environments. The involvement of the LGN in this rich, contextually informed visual processing-despite showing minimal feedforward selectivity for visual features [19, 20]-underscores the role of recurrent processing at the earliest stages of visual processing.
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http://dx.doi.org/10.1016/j.cub.2019.04.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625759PMC
June 2019

Acute pancreatitis and vasoplegic shock associated with leptospirosis - a case report and review of the literature.

BMC Infect Dis 2019 May 8;19(1):395. Epub 2019 May 8.

Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

Background: Leptospirosis or Weil's disease is caused by pathogenic spirochete bacteria called Leptospira. It is considered the most common zoonosis in the world and is usually transmitted by urine of rodents and dogs with an incubation time of 7-14 days. The clinical spectrum ranges from a subclinical infection to a fulminant septic course.

Case Presentation: Here, we report the case of a German patient with acute pancreatitis associated with Leptospira interrogans causing fulminant septic shock. The patient was successfully treated with intravenous antibiotics and left the hospital fully recovered after 18 days.

Conclusions: To our knowledge, this is the first case of leptospirosis with acute pancreatitis as the leading clinical manifestation in Central Europe. Serologic and molecular genetic tests for leptospirosis should be considered, if no other causes for pancreatitis can be identified.
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http://dx.doi.org/10.1186/s12879-019-4040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507051PMC
May 2019

V1 microcircuit dynamics: altered signal propagation suggests intracortical origins for adaptation in response to visual repetition.

J Neurophysiol 2019 05 27;121(5):1938-1952. Epub 2019 Mar 27.

Department of Psychology, Center for Integrative and Cognitive Neuroscience, and Vanderbilt Vision Research Center, Vanderbilt University , Nashville, Tennessee.

Repetitive visual stimulation profoundly changes sensory processing in the primary visual cortex (V1). We show how the associated adaptive changes are linked to an altered flow of synaptic activation across the V1 laminar microcircuit. Using repeated visual stimulation, we recorded layer-specific responses in V1 of two fixating monkeys. We found that repetition-related spiking suppression was most pronounced outside granular V1 layers that receive the main retinogeniculate input. This repetition-related response suppression was robust to alternating stimuli between the eyes, in line with the notion that repetition-related adaptation is predominantly of cortical origin. Most importantly, current source density (CSD) analysis, which provides an estimate of local net depolarization, revealed that synaptic processing during repeated stimulation was most profoundly affected within supragranular layers, which harbor the bulk of cortico-cortical connections. Direct comparison of the temporal evolution of laminar CSD and spiking activity showed that stimulus repetition first affected supragranular synaptic currents, which translated into a reduction of stimulus-evoked spiking across layers. Together, these results suggest that repetition induces an altered state of intracortical processing that underpins visual adaptation. Our survival depends on our brains rapidly adapting to ever changing environments. A well-studied form of adaptation occurs whenever we encounter the same or similar stimuli repeatedly. We show that this repetition-related adaptation is supported by systematic changes in the flow of sensory activation across the laminar cortical microcircuitry of primary visual cortex. These results demonstrate how adaptation impacts neuronal interactions across cortical circuits.
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http://dx.doi.org/10.1152/jn.00113.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589708PMC
May 2019

Binocular Modulation of Monocular V1 Neurons.

Curr Biol 2019 02 17;29(3):381-391.e4. Epub 2019 Jan 17.

Department of Psychology, College of Arts and Science, Vanderbilt Vision Research Center, Center for Integrative and Cognitive Neuroscience, Vanderbilt University, 2201 West End Avenue, Nashville, TN 37203, USA. Electronic address:

In humans and other primates, sensory signals from each eye remain separated until they arrive in the primary visual cortex (V1), but their exact meeting point is unknown. In V1, some neurons respond to stimulation of only one eye (monocular neurons), while most neurons respond to stimulation of either eye (binocular neurons). The main input layers of V1 contain most of the monocular neurons while binocular neurons dominate the layers above and below. This observation has given rise to the idea that the two eyes' signals remain separate until they converge outside V1's input layers. Here, we show that, despite responding to only one eye, monocular neurons in all layers, including the input layers, of V1 discriminate between stimulation of their driving eye alone and stimulation of both eyes. Some monocular V1 neurons' responses were significantly enhanced, or facilitated, when both eyes were stimulated. Binocular facilitation within V1's input layers tended to occur at the onset of the visual response, which could be explained by converging thalamocortical inputs. However, most V1 monocular neurons were significantly reduced, or suppressed, to binocular stimulation. In contrast to facilitation, binocular suppression occurred several milliseconds following the onset of the visual response, suggesting that the bulk of binocular modulation involves cortical inhibition. These findings, combined, suggest that binocular signals arise at an earlier processing stage than previously appreciated, as even so-called monocular neurons in V1's input layers encode what is shown to both eyes.
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http://dx.doi.org/10.1016/j.cub.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363852PMC
February 2019

Plasmodium falciparum.

Trends Parasitol 2019 06 27;35(6):481-482. Epub 2018 Dec 27.

Center for Advanced Microscopy, The Australian National University, Canberra ACT, Australia.

Plasmodium falciparum is the etiological agent of malaria tropica, the leading cause of death due to a vector-borne infectious disease, claiming 0.5 million lives every year. The single-cell eukaryote undergoes a complex life cycle and is an obligate intracellular parasite of hepatocytes (clinically silent) and erythrocytes (disease causing). An infection can progress to a wide range of pathologies, including severe anemia and cerebral malaria, which can lead to death. P. falciparum repeatedly replicates over the course of 48h inside erythrocytes, resulting in exponential growth and rapid disease progression. As the single most important infectious disease afflicting children, no other pathogen has exerted a higher selection pressure on the human genome. Over 20 polymorphisms, including the sickle-cell trait, have been selected in human populations, despite severe fitness costs, since they offer protection against fatal P. falciparum infections. No effective vaccine exists, but several curative treatments are available.
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http://dx.doi.org/10.1016/j.pt.2018.11.010DOI Listing
June 2019

Borane-Catalyzed Synthesis of Quinolines Bearing Tetrasubstituted Stereocenters by Hydride Abstraction-Induced Electrocyclization.

Chemistry 2018 Nov 5;24(61):16287-16291. Epub 2018 Oct 5.

Department of Chemistry, University of Paderborn, Warburger Strasse 100, 33098, Paderborn, Germany.

The borane-catalyzed synthesis of quinoline derivatives bearing tetrasubstituted stereocenters from vinyl anilines has been developed. Mechanistic studies and quantum-mechanical investigations support the hydride abstraction/electrocyclization/hydride addition mechanism. The products were obtained in up to 99 % yield with a diastereoselectivity of >99 % in favour for the 3a-5-cis isomer.
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http://dx.doi.org/10.1002/chem.201804777DOI Listing
November 2018
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