Toward a Manifold Encoding Neural Responses

Understanding circuit properties from physiological data presents two challenges: (i) recordings do not reveal connectivity, and (ii) stimuli only exercise circuits to a limited extent. We address these challenges for the mouse visual system with a novel neural manifold obtained using unsupervised algorithms. Each point in our manifold is a neuron; nearby neurons respond similarly in time to similar parts of a stimulus ensemble. This ensemble includes drifting gratings and flows, i.e., patterns resembling what a mouse would “see” running through fields. Regarding (i), our manifold differs from the standard practice in computational neuroscience: embedding trials in neural coordinates. Topology matters: we infer that, if the circuit consists of separate components, the manifold is discontinuous (illustrated with retinal data). If there is significant overlap between circuits, the manifold is nearly-continuous (cortical data). Regarding (ii), most of the cortical manifold is not activated with conventional gratings, despite their prominence in laboratory settings. Our manifold suggests organizing cortical circuitry by a few specialized circuits for specific members of the stimulus ensemble, together with circuits involving ‘multi-stimuli’-responding neurons. To approach real circuits, local neighborhoods in the manifold are identified with actual circuit components. For retinal data, we show these components correspond to distinct ganglion cell types by their mosaic-like receptive field organization, while for cortical data, neighborhoods organize neurons by type (excitatory/inhibitory) and anatomical layer. In summary: the topology of neural organization reflects well the underlying anatomy and physiology of the retina and the visual cortex

Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti–Helicobacter pylori IgG Titers

Funding Information: Funding The Rotterdam Study I-II was supported by the Netherlands Organization of Scientific Research (NWO; 175.010.2005.011, 911-03-012), Research Institute for Diseases in the Elderly (RIDE; 014-93-015), Genomics Initiative/NWO (project no. 050-060-810), Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), Ministry of Education, Culture, and Science and Ministry for Health, Welfare, and Sports, European Commission, and the Municipality of Rotterdam. GenerationR was supported by Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, ZonMw (907.00303, 916.10159), NWO, and the Ministry for Health, Welfare and Sports. The Study of Health in Pomerania (SHIP) and SHIP-TREND were supported by Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung (109102), Deutsche Forschungsgemeinschaft (DFG GRK840-D2/E3/E4, MA 4115/1-2/3), Federal Ministry of Education and Research (BMBF GANI-MED 03IS2061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012), the European Union (EU-FP-7-EPCTM and EU-FP7-REGPOT-2010-1), AstraZeneca (unrestricted grant), the Federal Ministry of Education and Research, Siemens Healthcare, the Federal State of Mecklenburg–West Pomerania, and the University of Greifswald. The Framingham Heart Study was supported by National Institutes of Health grants N01-HC-25195, HHSN268201500001I, and 75N92019D00031 (to Boston University) and the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI). The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe projects were supported by the NHLBI (75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI grant N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population were supported by the State Ministry of Science, Research and Arts, Baden-Württemberg, Federal Ministry of Education and Research, and Federal Ministry of Family Affairs, Senior Citizens, Women and Youth. LATVIA was supported by the European Regional Development Fund (ERDF; 009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016), National Program for Research in Latvia, Ministry of Health (6-1396-2016), and Fundamental and Applied Research Projects Program in Latvia (project no. lzp-2018/1-0135). Funding Information: Conceptualization: Linda Broer, Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Ben Schöttker, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Raitis Peculis, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, André Uitterlinden, Ernst J. Kuipers, Maikel P. Peppelenbosch, and additional members of Rotterdam Study I-II, GenerationR, Study of Health in Pomerania, Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population, and LATVIA cohorts not directly involved in this manuscript. Methodology: all authors. Investigation: all authors. Formal analysis of discovery: Linda Broer, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, and Edmond K. Kabagambe. Formal analysis of replication: Yan Zhang, Hannah Stocker, Hermann Brenner, Marcis Leja, Janis Klovins, and Raitis Peculis. Formal analysis of meta-analysis: Linda Broer. Project administration: Suk Yee Lam and Gwenny M. Fuhler. Resources: Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, Ernst J. Kuipers, and Maikel P. Peppelenbosch. Supervision: Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Gwenny M. Fuhler, Maikel P. Peppelenbosch, and André Uitterlinden. Visualization: Suk Yee Lam, Michiel C. Mommersteeg, Bingting Yu, Linda Broer, and Gwenny M. Fuhler. Writing—original draft: Suk Yee Lam, Michiel C. Mommersteeg, and Gwenny M. Fuhler. Writing—reviewing and editing: all authors. Publisher Copyright: © 2022 The Author(s)Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.publishersversionPeer reviewe

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Sense of social support in chonic pain patients

Statistical data show that one in five adults of the European citizen suffer from some type of chronic pain. One of the most common types of chronic pain is chronic low back and neck pain. Emotional factors are currently viewed as important determinants in pain perception and behaviour. The perceived social and emotional support have impact to the individual’s adaptation to chronic disease (Cohen, Wills, 1985). The material: 110 chronic low back pain (CLBP) patients (48 male and 62 female; in age from 24 to 60 years, mean: 44.2±8, 0) and pilot study of 23 chronic neck pain (CNP) patients (19 female and 4 male; in age from 35 to 60 years, mean: 48, 1 ±6. The assessment methods: structured interview; Hospital Anxiety and Depression Scale (HADS). SF-36 ® Health Survey: assessment of emotional and social support. Results and conclusions: CLBP patients in presence of symptoms of depression and elevated level of anxiety matched for socio-demographic features had less sense of social support and marked pain impact to daily activities, lower self rating health relating quality of life. In CLBP patients the sense of social and emotional support had relevant interaction with level of participation in daily activities both in patients with and without mental health problems. This fact has to be considered in process of rehabilitation and in managing of health care of CLBP patients. The results of CNP patients pilot study revealed interesting trend that chronic back and neck pain patients seems to be quite different according to sense of social and emotional support, therefore sense of social and emotional support in different chronic pain patients need further research to improve the process and results of rehabilitation in these patients

An ADP-ribosyltransferase toxin kills bacterial cells by modifying structured non-coding RNAs

ADP-ribosyltransferases (ARTs) were among the first identified bacterial virulence factors. Canonical ART toxins are delivered into host cells where they modify essential proteins, thereby inactivating cellular processes and promoting pathogenesis. Our understanding of ARTs has since expanded beyond protein-targeting toxins to include antibiotic inactivation and DNA damage repair. Here, we report the discovery of RhsP2 as an ART toxin delivered between competing bacteria by a type VI secretion system of Pseudomonas aeruginosa. A structure of RhsP2 reveals that it resembles protein-targeting ARTs such as diphtheria toxin. Remarkably, however, RhsP2 ADP-ribosylates 2'-hydroxyl groups of double-stranded RNA, and thus, its activity is highly promiscuous with identified cellular targets including the tRNA pool and the RNA-processing ribozyme, ribonuclease P. Consequently, cell death arises from the inhibition of translation and disruption of tRNA processing. Overall, our data demonstrate a previously undescribed mechanism of bacterial antagonism and uncover an unprecedented activity catalyzed by ART enzymes

Large-scale interrogation of retinal cell functions by 1-photon light-sheet microscopy

Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. We present a 1-photon light-sheet imaging system that can measure the activity in hundreds of neurons in the ex&nbsp;vivo retina over a large field of view while presenting visual stimuli. This allows for a reliable functional classification of different retinal cell types. We also demonstrate that the system has sufficient resolution to image calcium entry at individual synaptic release sites across the axon terminals of dozens of simultaneously imaged bipolar cells. The simple design, large field of view, and fast image acquisition make this a powerful system for high-throughput and high-resolution measurements of retinal processing at a fraction of the cost of alternative approaches