Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

Uncovering atherosclerotic cardiovascular disease by PET imaging.

Assessing atherosclerosis severity is essential for precise patient stratification. Specifically, there is a need to identify patients with residual inflammation because these patients remain at high risk of cardiovascular events despite optimal management of cardiovascular risk factors. Molecular imaging techniques, such as PET, can have an essential role in this context. PET imaging can indicate tissue-based disease status, detect early molecular changes and provide whole-body information. Advances in molecular biology and bioinformatics continue to help to decipher the complex pathogenesis of atherosclerosis and inform the development of imaging tracers. Concomitant advances in tracer synthesis methods and PET imaging technology provide future possibilities for atherosclerosis imaging. In this Review, we summarize the latest developments in PET imaging techniques and technologies for assessment of atherosclerotic cardiovascular disease and discuss the relationship between imaging readouts and transcriptomics-based plaque phenotyping.

Correction: A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.

[This corrects the article DOI: 10.1371/journal.ppat.1011517.].

A ubiquitous spectrolaminar motif of local field potential power across the primate cortex.

The mammalian cerebral cortex is anatomically organized into a six-layer motif. It is currently unknown whether a corresponding laminar motif of neuronal activity patterns exists across the cortex. Here we report such a motif in the power of local field potentials (LFPs). Using laminar probes, we recorded LFPs from 14 cortical areas across the cortical hierarchy in five macaque monkeys. The laminar locations of recordings were histologically identified by electrolytic lesions. Across all areas, we found a ubiquitous spectrolaminar pattern characterized by an increasing deep-to-superficial layer gradient of high-frequency power peaking in layers 2/3 and an increasing superficial-to-deep gradient of alpha-beta power peaking in layers 5/6. Laminar recordings from additional species showed that the spectrolaminar pattern is highly preserved among primates-macaque, marmoset and human-but more dissimilar in mouse. Our results suggest the existence of a canonical layer-based and frequency-based mechanism for cortical computation.

Combination of high resolution MRI with 3D-printed needle guides for ex vivo myocardial biopsies.

Magnetic resonance imaging (MRI) provides a multitude of techniques to detect and characterize myocardial infarction. To correlate MRI findings with histology, in most cases terminal animal studies are performed; however, precise extraction and spatial correlation of myocardial tissue samples to MRI image data is difficult. In this proof of concept study, we present a 3D-printing technique to facilitate the extraction of tissue samples from myocardial regions. Initially, seven pig hearts embedded in formaldehyde were imaged on a clinical 3 T system to define biopsy targets on high resolution ex vivo images. Magnitude images and R2*-maps acquired with a 3D multi-echo gradient echo sequence and 0.58 mm isotropic resolution were used to create digital models of the cardiac anatomy. Biopsy guides were 3D-printed to steer the extraction of myocardial samples. In total, 61 tissue samples were extracted with an average offset of the tissue sample location from the target location of 0.59 ± 0.36 mm. This offset was not dependent on the distance of the target point to the epicardial surface. Myocardial tissue could be extracted from all samples. The presented method enables extraction of myocardial tissue samples that are selected by ex vivo MRI with submillimeter precision.

Cardioaortic dimensions in German landrace pigs derived from cardiac magnetic resonance imaging.

Pigs are frequently applied as animal models in cardiovascular research due to their anatomical and physiological similarity to humans. For study planning and refinement, precise knowledge of the cardioaortic dimensions is essential. In a retrospective single-center study, the cardioaortic dimensions and left ventricular function of German Landrace pigs were assessed using cardiac MRI. All parameters were compared between male and female pigs and analyzed for correlation with body weight. In total, 15 pigs were included (7 male and 8 female, weight 60.9 ± 7.0 kg). The left ventricle revealed an end-diastolic diameter of 50.5 ± 4.4 mm and an ejection fraction of 51.2 ± 9.8%. The diameters of the ascending and descending aorta were 21.3 ± 2.3 and 16.2 ± 1.4 mm, respectively. There were no significant differences between male and female pigs, except that males had a smaller end-diastolic left ventricular volume (p = 0.041). A moderate correlation was found between body weight and the aortic annulus diameter (R = 0.57, p = 0.027). In conclusion, cardiac MRI allows precise quantification of porcine cardioaortic dimensions. For medical device testing, size differences between pigs and humans should be considered.

Comparing balloon-expandable and self-expanding transfemoral transcatheter aortic valve replacement based on subgroups in Germany 2019/2020.

BACKGROUND: Previously, overall comparable outcomes were seen for balloon-expandable (BE) or self-expanding (SE) transfemoral transcatheter aortic valve replacement (TAVR). However, subgroup analyses based on large case numbers are still needed. METHODS: German national data of all BE and SE transfemoral TAVR treating aortic valve stenosis in 2019 and 2020 were analysed. We then compared different outcomes and performed a subgroup analysis for the endpoint in-hospital mortality. RESULTS: Overall, 46,243 TAVR were analysed, 19,910 BE, and 26,333 SE. Patients in the SE group had a significantly higher logistic EuroSCORE (13.61 vs 12.66%, p < 0.001), age (81.55 vs 79.99a, p < 0.001), and proportion of women (54.82 vs 40.06%, p < 0.001). Both groups showed a similar in-hospital mortality with 2.37% in BE and 2.35% in SE (p = 0.916). In-hospital mortality also did not differ significantly after risk adjustment (OR = 0.98 [0.86, 1.13], p = 0.799). Patients in the SE group had a significantly lower risk of major bleeding (OR = 0.83 [0.73, 0.95], p = 0.006), but a significantly higher risk of stroke (OR = 1.38 [1.19, 1.59], p < 0.001), delirium (OR = 1.15 [1.06, 1.24], p = 0.001), and permanent pacemaker implantation (OR = 1.29 [1.21, 1.37], p < 0.001). In the subgroup analysis of in-hospital mortality, there were no significant differences in any of the observed subgroups (age < 75/75-79/80-84/ ≥ 85a, logistic EuroSCORE < 4/4- < 9/ ≥ 9, gender, NYHA III/IV, previous CABG, peripheral vascular disease, COPD, pulmonary hypertension, renal disease GFR < 30 ml/min, and diabetes mellitus). CONCLUSION: In the direct comparison of balloon-expandable and self-expanding TAVR, there are no differences for in-hospital mortality in subgroups.

Analysis of Plasmodium falciparum Mitochondrial Electron Transport Chain Activity Using Seahorse XFe96 Extracellular Flux Assays.

The mitochondrial electron transport chain (ETC) is a multi-component pathway that mediates the transfer of electrons from metabolic reactions that occur in the mitochondrion to molecular oxygen (O2). The ETC contributes to numerous cellular processes, including the generation of cellular ATP through oxidative phosphorylation, serving as an electron sink for metabolic pathways such as de novo pyrimidine biosynthesis and for maintaining mitochondrial membrane potential. Proper functioning of the mitochondrial ETC is necessary for the growth and survival of apicomplexan parasites including Plasmodium falciparum, a causative agent of malaria. The mitochondrial ETC of P. falciparum is an attractive target for antimalarial drugs, due to its essentiality and its differences from the mammalian ETC. To identify novel P. falciparum ETC inhibitors, we have established a real-time assay to assess ETC function, which we describe here. This approach measures the O2 consumption rate (OCR) of permeabilized P. falciparum parasites using a Seahorse XFe96 flux analyzer and can be used to screen compound libraries for the identification of ETC inhibitors and, in part, to determine the targets of those inhibitors. Key features • With this protocol, the effects of candidate inhibitors on mitochondrial O2 consumption in permeabilized asexual P. falciparum parasites can be tested in real time. • Through the sequential injection of inhibitors and substrates into the assay, the molecular targets of candidate inhibitors in the ETC can, in part, be determined. • The assay is applicable for both drug discovery approaches and enquiries into a fundamental aspect of parasite mitochondrial biology.

Feedforward attentional selection in sensory cortex.

Salient objects grab attention because they stand out from their surroundings. Whether this phenomenon is accomplished by bottom-up sensory processing or requires top-down guidance is debated. We tested these alternative hypotheses by measuring how early and in which cortical layer(s) neural spiking distinguished a target from a distractor. We measured synaptic and spiking activity across cortical columns in mid-level area V4 of male macaque monkeys performing visual search for a color singleton. A neural signature of attentional capture was observed in the earliest response in the input layer 4. The magnitude of this response predicted response time and accuracy. Errant behavior followed errant selection. Because this response preceded top-down influences and arose in the cortical layer not targeted by top-down connections, these findings demonstrate that feedforward activation of sensory cortex can underlie attentional priority.

Catheter based left atrial appendage closure in-hospital outcomes in Germany from 2016 to 2020.

BACKGROUND: New and refined catheter based left atrial appendage (LAA) closure devices have been introduced in the past decade. The procedure can be performed using either an endocardial occlusion device or an epicardial loop stitch. We aimed to analyzed recent procedural safety. METHODS: Catheter based LAA closures were identified in a complete nationwide German dataset via ICD and OPS codes from 2016 to 2020. RESULTS: From 2016 to 2020, 28,039 endocardial and 213 epicardial occlusions were performed. Numbers of endocardial procedures increased from 5259 in 2016 to 5917 in 2020 (p = 0.020) in 387 centers with shifting of patients' characteristics towards older age (ß = 0.29, p < 0.001), more heart failure (ß = 1.01, p < 0.001) and renal disease (ß = 0.67, p = 0.001) and without a significant trend for in-hospital safety except more bleeding (ß = 0.12, p = 0.05). In-hospital major adverse cardiac and cerebrovascular events (MACCE) or pericardial puncture were independent on center procedure numbers. The loop stitch procedure was performed in 15 centers. Patients were younger (76.17 ± 8.16 vs. 73.16 ± 8.99, p < 0.001) and had a lower comorbidity index (2.29 ± 1.93 vs. 1.92 ± 1.64, p = 0.005). Adjusted risk difference for pericardial effusion (8.04%; 95% CI 3.01-13.08%; p = 0.002) and pericardial puncture (6.60%; 95% CI 3.85-9.35%; p < 0.001) was higher for the loop stitch procedure, while risk of bleeding (- 1.85%; 95% CI - 3.01 to - 0.69%; p = 0.002), intracerebral bleeding (- 0.37%; 95% CI - 0.59 to - 0.15%; p = 0.001) and shock (- 1.41%; 95% CI - 2.44 to - 0.39%; p = 0.007) was lower. No significant difference was observed for in-hospital MACCE. CONCLUSIONS: Endocardial occlusion was the major catheter based LAA closure procedure in Germany without improvements in in-hospital safety from 2016 to 2020. In-hospital MACCE was independent on endocardial LAAC center volumes. Conclusions on the comparison between the two procedure types must be made cautious as the LAA loop stitch occlusion was utilized limited in a minor number of centers. Catheter based left atrial appendage closure in-hospital outcomes in Germany from 2016 to 2020.

A role for ocular dominance in binocular integration.

Neurons in the primate primary visual cortex (V1) combine left- and right-eye information to form a binocular output. Controversy surrounds whether ocular dominance, the preference of these neurons for one eye over the other, is functionally relevant. Here, we demonstrate that ocular dominance impacts gain control during binocular combination. We recorded V1 spiking activity while monkeys passively viewed grating stimuli. Gratings were either presented to one eye (monocular), both eyes with the same contrasts (binocular balanced), or both eyes with different contrasts (binocular imbalanced). We found that contrast placed in a neuron's dominant eye was weighted more strongly than contrast placed in a neuron's non-dominant eye. This asymmetry covaried with neurons' ocular dominance. We then tested whether accounting for ocular dominance within divisive normalization improves the fit to neural data. We found that ocular dominance significantly improved model performance, with interocular normalization providing the best fits. These findings suggest that V1 ocular dominance is relevant for response normalization during binocular stimulation.

Multiparametric Immunoimaging Maps Inflammatory Signatures in Murine Myocardial Infarction Models.

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed in vivo multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoe-/-mice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using 18F-fluorothymidine and 18F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in Apoe-/- mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts.

Does V1 response suppression initiate binocular rivalry?

During binocular rivalry (BR) only one eye's view is perceived. Neural underpinnings of BR are debated. Recent studies suggest that primary visual cortex (V1) initiates BR. One trigger might be response suppression across most V1 neurons at the onset of BR. Here, we utilize a variant of BR called binocular rivalry flash suppression (BRFS) to test this hypothesis. BRFS is identical to BR, except stimuli are shown with a ∼1s delay. If V1 response suppression was required to initiate BR, it should occur during BRFS as well. To test this, we compared V1 spiking in two macaques observing BRFS. We found that BRFS resulted in response facilitation rather than response suppression across V1 neurons. However, BRFS still reduces responses in a subset of V1 neurons due to the adaptive effects of asynchronous stimulus presentation. We argue that this selective response suppression could serve as an alternate initiator of BR.

A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.

Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.

Decreased level of serum NT-proCNP associates with disease severity in COVID-19.

BACKGROUND: C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. METHODS: In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). RESULTS: The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. CONCLUSIONS: Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021.

Rapid adaptation of primate LGN neurons to drifting grating stimulation.

The visual system needs to dynamically adapt to changing environments. Much is known about the adaptive effects of constant stimulation over prolonged periods. However, there are open questions regarding adaptation to stimuli that are changing over time, interrupted, or repeated. Feature-specific adaptation to repeating stimuli has been shown to occur as early as primary visual cortex (V1), but there is also evidence for more generalized, fatigue-like adaptation that might occur at an earlier stage of processing. Here, we show adaptation in the lateral geniculate nucleus (LGN) of awake, fixating monkeys following brief (1 s) exposure to repeated cycles of a 4-Hz drifting grating. We examined the relative change of each neuron's response across successive (repeated) grating cycles. We found that neurons from all cell classes (parvocellular, magnocellular, and koniocellular) showed significant adaptation. However, only magnocellular neurons showed adaptation when responses were averaged to a population response. In contrast to firing rates, response variability was largely unaffected. Finally, adaptation was comparable between monocular and binocular stimulation, suggesting that rapid LGN adaptation is monocular in nature.NEW & NOTEWORTHY Neural adaptation can be defined as reduction of spiking responses following repeated or prolonged stimulation. Adaptation helps adjust neural responsiveness to avoid saturation and has been suggested to improve perceptual selectivity, information transmission, and predictive coding. Here, we report rapid adaptation to repeated cycles of gratings drifting over the receptive field of neurons at the earliest site of postretinal processing, the lateral geniculate nucleus of the thalamus.

Near-field potentials index local neural computations more accurately than population spiking.

Local field potentials (LFP) are low-frequency extracellular voltage fluctuations thought to primarily arise from synaptic activity. However, unlike highly localized neuronal spiking, LFP is spatially less specific. LFP measured at one location is not entirely generated there due to far-field contributions that are passively conducted across volumes of neural tissue. We sought to quantify how much information within the locally generated, near-field low-frequency activity (nfLFP) is masked by volume-conducted far-field signals. To do so, we measured laminar neural activity in primary visual cortex (V1) of monkeys viewing sequences of multifeatured stimuli. We compared information content of regular LFP and nfLFP that was mathematically stripped of volume-conducted far-field contributions. Information content was estimated by decoding stimulus properties from neural responses via spatiotemporal multivariate pattern analysis. Volume-conducted information differed from locally generated information in two important ways: (1) for stimulus features relevant to V1 processing (orientation and eye-of-origin), nfLFP contained more information. (2) in contrast, the volume-conducted signal was more informative regarding temporal context (relative stimulus position in a sequence), a signal likely to be coming from elsewhere. Moreover, LFP and nfLFP differed both spectrally as well as spatially, urging caution regarding the interpretations of individual frequency bands and/or laminar patterns of LFP. Most importantly, we found that population spiking of local neurons was less informative than either the LFP or nfLFP, with nfLFP containing most of the relevant information regarding local stimulus processing. These findings suggest that the optimal way to read out local computational processing from neural activity is to decode the local contributions to LFP, with significant information loss hampering both regular LFP and local spiking. Author's Contributions: Conceptualization, D.A.T., J.A.W, and A.M.; Data Collection, J.A.W., M.A.C., K.D.; Formal Analysis, D.A.T. and J.A.W.; Data Visualization, D.A.T. and J.A.W.; Original Draft, D.A.T., J.A.W., and A.M.; Revisions and Final Draft, D.A.T., J.A.W., M.A.C., K.D., M.T.W., A.M.B., and A.M. Competing Interests: The authors declare no conflicts of interest.

Plasmodium falciparum gametocytes display global chromatin remodelling during sexual differentiation.

BACKGROUND: The protozoan malaria parasite Plasmodium falciparum has a complex life cycle during which it needs to differentiate into multiple morphologically distinct life forms. A key process for transmission of the disease is the development of male and female gametocytes in the human blood, yet the mechanisms determining sexual dimorphism in these haploid, genetically identical sexual precursor cells remain largely unknown. To understand the epigenetic program underlying the differentiation of male and female gametocytes, we separated the two sexual forms by flow cytometry and performed RNAseq as well as comprehensive ChIPseq profiling of several histone variants and modifications. RESULTS: We show that in female gametocytes the chromatin landscape is globally remodelled with respect to genome-wide patterns and combinatorial usage of histone variants and histone modifications. We identified sex specific differences in heterochromatin distribution, implicating exported proteins and ncRNAs in sex determination. Specifically in female gametocytes, the histone variants H2A.Z/H2B.Z were highly enriched in H3K9me3-associated heterochromatin. H3K27ac occupancy correlated with stage-specific gene expression, but in contrast to asexual parasites this was unlinked to H3K4me3 co-occupancy at promoters in female gametocytes. CONCLUSIONS: Collectively, we defined novel combinatorial chromatin states differentially organising the genome in gametocytes and asexual parasites and unravelled fundamental, sex-specific differences in the epigenetic code. Our chromatin maps represent an important resource for future understanding of the mechanisms driving sexual differentiation in P. falciparum.