Max Planck Institute Research Articles

Kovač, Uroš. The precarity of masculinity: football, Pentecostalism, and transnational aspirations in Cameroon. xiv, 173 pp., maps, illus., bibliogr. Oxford, New York: Berghahn Books, 2022. £99.00 (cloth)

Journal of the Royal Anthropological InstituteVolume 29, Issue 2 p. 478-479 Book and film reviews Kovač, Uroš. The precarity of masculinity: football, Pentecostalism, and transnational aspirations in Cameroon. xiv, 173 pp., maps, illus., bibliogr. Oxford, New York: Berghahn Books, 2022. £99.00 (cloth) Mario Schmidt, Mario Schmidt Max Planck Institute for Social Anthropology (Halle)Search for more papers by this author Mario Schmidt, Mario Schmidt Max Planck Institute for Social Anthropology (Halle)Search for more papers by this author First published: 10 May 2023 https://doi.org/10.1111/1467-9655.13939Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume29, Issue2June 2023Pages 478-479 RelatedInformation

Scientists pull new molecules from old teeth

A group of researchers has synthesized a never-before-seen natural product found by scraping crusted gunk from Neanderthal teeth. An international team led by Pierre Stallforth from the Hans Knöll Institute and Christina Warinner of the Max Planck Institute for Evolutionary Anthropology mined calcified dental plaque for DNA fragments, pieced these bits together to reconstruct ancient bacterial genes, and then synthesized a pair of small molecules called paleofurans ( Science 2023, DOI: 10.1126/science.adf5300 ). This is the first time scientists have reassembled and then used ancient DNA as a blueprint to synthesize natural products. The method not only shows how bacteria swam through Paleolithic mouths but also opens up the search for potentially useful natural products to billions of years of history. Natural products are potential sources of new antibiotics and other drugs. But scientists have been limited to searching sources living in the current time. “We’re adding a time dimension

Evaluation of Earth System Models outputs over the continental Portuguese coast: A historical comparison between CMIP5 and CMIP6

In the last decades, climate change has been accelerating, affecting, directly and indirectly, the environment, animal habitats, and daily human life. Earth System Models (ESMs) are valuable tools for studying these impacts, and their performance over coastal regions is critical for understanding how physical and biogeochemical processes are evolving through time and how they may change in the future. The continental Portuguese coast, characterized by an important upwelling system, hosts highly productive and nutrient-rich regions with a large diversity of transitional habitats and systems. Therefore, this study aims to evaluate and score the ESMs from the 5th and 6th phases of the Coupled Model Intercomparison Project that better reproduce, simultaneously, physical and biogeochemical ocean properties along the continental Portuguese coast. The analysis was carried out through the computation of a score (SR) between CMIP historical outputs and data from the Iberian-Biscay-Ireland ocean reanalysis system at four selected locations along the coast, considering two physical and four biochemical variables. Results reveal that ESMs perform better for the physical properties than for the biochemical ones, as well as lower differences and variance between CMIP6 models, reflecting an improvement from CMIP5. The Max Planck Institute (MPI) models obtained the best overall classification by delivering a consistently good performance for all variables.

Genome secrets of extinct hominids, or can paleogenomics answer the question: humankind, who we are? Nobel Prize in Physiology or Medicine 2022

The Nobel Prize in Physiology or Medicine 2022 was awarded to Professor Svante Pääbo, a Swedish­ paleogenetic researcher, specialist in the field of evolutionary genetics, Director of the Department of Evolutionary Genetics at the Max Planck Institute for Evolutionary Anthropology of Leipzig (Germany), for “discoveries concerning the genomes of extinct hominids and human evolution”. Explaining the significance of S. Pääbo’s work, the Nobel Committee noted that “he pioneered the methods to isolate and analyze DNA from archaic bone remains. In ancient bones, DNA has decayed, been chemically damaged and massively contaminated with DNA from bacteria and contemporary humans who work with the samples. Having utilized modern genetic methods, S. Pääbo created his own methods of sequencing the ancient DNA”. Keywords: genome, hominids, human evolution, Nobel Prize in Physiology or Medicine 2022, Svante Pääbo

Red Nucleus Volume Decrease in Healthy Aging (P12-6.003)

<h3>Objective:</h3> To investigate age-related red nucleus volume differences associated with healthy aging. <h3>Background:</h3> It is essential to identify and distinguish the subclinical neurodegenerative changes undetectable for clinical evaluation from the normal evolution of brain structure and function. Red Nucleus controls movement velocity encoding, gait and project to both cortical regions and the spinal cord. <h3>Design/Methods:</h3> The study population consists of 228 healthy participants from the Max Planck Institut Leipzig Mind-Brain-Body Dataset LEMON. Age was provided as a 5-year range. MRI imaging included single 3D T2-weighted Sagittal acquisition consisting of 176 slices, TR=3200ms, TE=409ms, FA=variable, pre-scan normalization, echo spacing=3.42 ms, bandwidth=751 Hz/pixel, FOV=256 mm, voxel size=1 mm isotropic, GRAPPA acceleration factor 2, duration=4min 43s. Segmentation of the red Nucleus used the pBrain algorithm relying on the following steps: denoising, registration, inhomogeneity correction, intensity standardization, cropping, superresolution, and non-linear registration to identify the location and volume of the red Nucleus measured as the sum of left and right nuclei. The statistical analysis relied on R-CRAN 3.6.3 and R-Studio 2022.07.2. <h3>Results:</h3> Demographic characteristics: younger population (N=154, 25.1±3.1 years, range 20–35 years, 45 female) and an elderly population (N=74, 67.6±4.7 years, range 59–77 years, 37 female). Segmentation succeeded in 198 individuals. The volume of the Red Nucleus was normally distributed (Lillie.test) and had a mean volume of 498±84 mm³. The relative red nucleus volume to intracranial volume was 0.034±0.005. The correlation coefficient for the 5-year age-range period and red nucleus volume in mm³ was R²=−0.62 p&lt; 0.001. The correlation coefficient for the 5-year age-range period and red nucleus volume relative to the intracranial volume was R²=−0.60 p&lt; 0.001. <h3>Conclusions:</h3> Early identification of degenerative changes in the brain using non-invasive and widely available MRI sequences is vital for diagnosis and preventive therapies. Quantifying brain iron might improve the precise determination of red nucleus signal and volume evolution. <b>Disclosure:</b> Dr. Pawlak has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Surgalign . Dr. Pawlak has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Pawlak has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Inteneural Networks Inc. Dr. Pawlak has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for RSQ. Dr. Pawlak has received publishing royalties from a publication relating to health care. Ms. CHIANG has nothing to disclose. Miss Hamada has nothing to disclose.

Free-viewing gaze patterns reveal a mood-congruency bias in MDD during an affective fMRI/eye-tracking task

Major depressive disorder (MDD) has been related to abnormal amygdala activity during emotional face processing. However, a recent large-scale study (n = 28,638) found no such correlation, which is probably due to the low precision of fMRI measurements. To address this issue, we used simultaneous fMRI and eye-tracking measurements during a commonly employed emotional face recognition task. Eye-tracking provide high-precision data, which can be used to enrich and potentially stabilize fMRI readouts. With the behavioral response, we additionally divided the active task period into a task-related and a free-viewing phase to explore the gaze patterns of MDD patients and healthy controls (HC) and compare their respective neural correlates. Our analysis showed that a mood-congruency attentional bias could be detected in MDD compared to healthy controls during the free-viewing phase but without parallel amygdala disruption. Moreover, the neural correlates of gaze patterns reflected more prefrontal fMRI activity in the free-viewing than the task-related phase. Taken together, spontaneous emotional processing in free viewing might lead to a more pronounced mood-congruency bias in MDD, which indicates that combined fMRI with eye-tracking measurement could be beneficial for our understanding of the underlying psychopathology of MDD in different emotional processing phases.Trial Registration: The BeCOME study is registered on ClinicalTrials (gov: NCT03984084) by the Max Planck Institute of Psychiatry in Munich, Germany.

Improving statistical projections of ocean dynamic sea-level change using pattern recognition techniques

Abstract. Regional emulation tools based on statistical relationships, such as pattern scaling, provide a computationally inexpensive way of projecting ocean dynamic sea-level change for a broad range of climate change scenarios. Such approaches usually require a careful selection of one or more predictor variables of climate change so that the statistical model is properly optimized. Even when appropriate predictors have been selected, spatiotemporal oscillations driven by internal climate variability can be a large source of statistical model error. Using pattern recognition techniques that exploit spatial covariance information can effectively reduce internal variability in simulations of ocean dynamic sea level, significantly reducing random errors in regional emulation tools. Here, we test two pattern recognition methods based on empirical orthogonal functions (EOFs), namely signal-to-noise maximizing EOF pattern filtering and low-frequency component analysis, for their ability to reduce errors in pattern scaling of ocean dynamic sea-level change. We use the Max Planck Institute Grand Ensemble (MPI-GE) as a test bed for both methods, as it is a type of initial-condition large ensemble designed for an optimal characterization of the externally forced response. We show that the two methods tested here more efficiently reduce errors than conventional approaches such as a simple ensemble average. For instance, filtering only two realizations by characterizing their common response to external forcing reduces the random error by almost 60 %, a reduction that is only achieved by averaging at least 12 realizations. We further investigate the applicability of both methods to single-realization modeling experiments, including four CMIP5 simulations for comparison with previous regional emulation analyses. Pattern filtering leads to a varying degree of error reduction depending on the model and scenario, ranging from more than 20 % to about 70 % reduction in global-mean root mean squared error compared with unfiltered simulations. Our results highlight the relevance of pattern recognition methods as a tool to reduce errors in regional emulation tools of ocean dynamic sea-level change, especially when one or only a few realizations are available. Removing internal variability prior to tuning regional emulation tools can optimize the performance of the statistical model, leading to substantial differences in emulated dynamic sea level compared to unfiltered simulations.

Transdiagnostic evaluation of epigenetic age acceleration and burden of psychiatric disorders

Different psychiatric disorders as well as exposure to adverse life events have individually been associated with multiple age-related diseases and mortality. Age acceleration in different epigenetic clocks can serve as biomarker for such risk and could help to disentangle the interplay of psychiatric comorbidity and early adversity on age-related diseases and mortality. We evaluated five epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge and DunedinPoAm) in a transdiagnostic psychiatric sample using epigenome-wide DNA methylation data from peripheral blood of 429 subjects from two studies at the Max Planck Institute of Psychiatry. Burden of psychiatric disease, represented by a weighted score, was significantly associated with biological age acceleration as measured by GrimAge and DunedinPoAm (R2-adj. 0.22 and 0.33 for GrimAge and DunedinPoAm, respectively), but not the other investigated clocks. The relation of burden of psychiatric disease appeared independent of differences in socioeconomic status and medication. Our findings indicate that increased burden of psychiatric disease may associate with accelerated biological aging. This highlights the importance of medical management of patients with multiple psychiatric comorbidities and the potential usefulness of specific epigenetic clocks for early detection of risk and targeted intervention to reduce mortality in psychiatric patients.

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Back to table of contents Previous article Next article EditorialsFull AccessGuilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune DisordersAndrew H. Miller, M.D., and Elisabeth B. Binder, M.D., Ph.D.Andrew H. MillerSearch for more papers by this author, M.D., and Elisabeth B. BinderSearch for more papers by this author, M.D., Ph.D.Published Online:1 Apr 2023https://doi.org/10.1176/appi.ajp.20230078AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail “A person is known by the company they keep”—AesopThe significant interrelationship between stress-related disorders, including posttraumatic stress disorder (PTSD), and autoimmune and inflammatory diseases provides compelling evidence that inflammation represents both a mechanism and a target for the treatment of these psychiatric conditions (1–3). Indeed, data indicate that stress-related neuroendocrine alterations can drive inflammatory responses that overlap with those seen in autoimmune and inflammatory disorders. For example, special attention has been paid to the disruptive effects of chronic or traumatic stress on the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system and their effects on the regulation of the inflammatory response. HPA axis hormones, notably cortisol, play an important role in restraining inflammation, while activation of the sympathetic nervous system has been shown to mobilize immune cells from the bone marrow and stimulate intracellular inflammatory signaling pathways, including the nuclear factor kappa B (NF-kB) pathway (1, 2, 4). Increased levels of inflammatory markers have been reliably reported in the peripheral blood of patients with stress-related disorders and PTSD, including increases in the acute-phase reactant C-reactive protein (CRP) and the inflammatory cytokines tumor necrosis factor (TNF), interleukin-1 beta, interleukin-6, and interferon gamma (5). Moreover, increased activation of inflammatory signaling pathways has been found in blood transcriptomic analyses of PTSD patients (2). Childhood trauma, a major risk factor for stress-related disorders and autoimmune diseases (6), has also been linked with inflammation, in part through epigenetic effects on relevant genes, including FKBP5, which not only plays a role in the sensitivity to cortisol through effects on the glucocorticoid receptor but also affects activation of NF-kB signaling pathways (7). Increased inflammation in turn has been shown to engage relevant brain circuits involved in anxiety and depression (4). Interestingly, while it is clear that stress-induced neuroendocrine disturbances can lead to increased inflammation and related behavioral changes, there is also evidence that inflammation prior to trauma can increase the likelihood of developing stress-related pathology (1). In a study of over 2,500 male U.S. marines, predeployment CRP levels significantly predicted postdeployment PTSD (8). These data suggest that an inflammatory bias is a risk factor for stress-related disorders and PTSD, and thus the arrow between stress-related disorders and inflammation points in both directions (1).Providing further support for the notion that stress-related disorders and inflammation are joined at the hip is the article by Zeng et al. (9) in this issue of the Journal. In this study, a variety of complementary analytic strategies were used to examine the genetic relationships between stress-related disorders, including PTSD, and autoimmune and inflammatory diseases, such as rheumatoid arthritis, ulcerative colitis, psoriasis, and insulin-dependent diabetes. In a large database of over 4 million individuals from Swedish nationwide registries, the authors observed not only a significant co-occurrence of these two types of disorders within individuals but also a co-occurrence of these two phenotypes in pairs of relatives. Their co-occurrence significantly increased as a function of ascending kinship, with a 51% greater likelihood of having both a stress-related disorder and an autoimmune disease in monozygotic twin pairs and a 28% and 16% greater likelihood in dizygotic twin pairs and full-sibling pairs, respectively. A similar increased likelihood of having an autoimmune disorder in individuals with a diagnosis of a stress-related disorder was found in the UK Biobank data, with a striking odds ratio of 2.35 (95% CI=1.90–2.91) for an autoimmune disease among individuals with an inpatient diagnosis of PTSD. This correlation on the phenotypic level was also accompanied by shared genetic risk. In fact, polygenic risk scores for stress-related disorders were associated with significantly increased risk for autoimmune diseases and vice versa. A positive genetic correlation (rg) of 0.26 was found between stress-related disorders and autoimmune disorders, and this correlation was even stronger for PTSD specifically (rg=0.39). The extent of this genetic correlation was as large as or larger than the one observed between PTSD and cardiovascular disease (rg=0.24) (10), further substantiating a genetic link between PTSD and diseases associated with inflammation, including both cardiovascular disease and autoimmune disorders. Ten genes and five functional gene modules were found to be shared between stress-related disorders and autoimmune diseases. Of note, the validity of the findings was further supported by the consistency of results when stress-related disorders (primarily adjustment disorders) and PTSD were considered separately and when each autoimmune or inflammatory disorder was analyzed individually. Overall, the findings have the advantage of the study’s having drawn from multiple databases and employing several strategies of genetic analyses, ultimately identifying commonalities at the molecular level as well as specific treatment targets for future studies. Finally, the results of the study confirm and extend other findings of genetic associations between psychiatric phenotypes, including PTSD, and immune-related phenotypes (2).The question then arises as to why these relationships between behavior and the immune system persist in the gene pool despite the detrimental consequences of both stress-related disorders and autoimmune and inflammatory diseases. One possibility is that these relationships derive from evolutionary pressures that required an immune and behavioral preparedness to address an ancestral environment rife with pathogens and predators that challenged survival to reproductive age (4, 11). Aggressive immune responses support fighting infection and wound healing, while hypervigilance can protect against future attack, especially in vulnerable individuals who are infected or wounded. Of note, administration of inflammatory stimuli has been reliably shown to activate threat-related neurocircuitry involving the dorsal anterior cingulate cortex, the insula, the hippocampus, and the amygdala (4). Nevertheless, although an aggressive immune response coupled with increased threat sensitivity and hyperarousal might have subserved evolutionary fitness in ancestral times, in the modern world, such evolutionary legacies may be less adaptive, and in conjunction with inflammation-associated lifestyles (characterized by obesogenic diets, sedentary activity, and social isolation) and exposure to trauma, they may contribute to rising rates of autoimmune and inflammatory diseases as well as stress-related disorders and PTSD.An important implication of the shared genetic associations between stress-related disorders and autoimmune disease, especially shared genes and gene modules, is the identification of immune targets for the treatment of PTSD and other stress-related disorders. It has been demonstrated that blocking inflammation with the anti-TNF drug infliximab reduces psychic anxiety and symptoms of anhedonia in otherwise medically healthy depressed patients with high baseline levels of CRP (12). Infliximab, which was one of the early biologic anticytokine drugs used to treat autoimmune diseases, was also found to reduce amygdala activation during an emotional face processing task using functional MRI in patients with inflammatory arthritis (13). Consistent with these findings, anticytokine therapies have also been reported to decrease symptoms of anxiety and depression in patients with a variety of autoimmune and inflammatory disorders (14). These data suggest that drugs used to treat autoimmune and inflammatory diseases may be relevant for the treatment of stress-related disorders such as PTSD. Of particular interest in this regard are drugs that are being developed for autoimmune diseases and target immunometabolism (15, 16). Upon activation, immune cells, especially monocytes, which are the primary mediators of the inflammatory response, shift their metabolism from the energy-efficient oxidative phosphorylation to the relatively energy-inefficient glycolysis. This metabolic shift allows rapid access to ATP that can be used for cellular growth and proliferation and for the production of inflammatory mediators, without the need to create more mitochondria, where oxidative phosphorylation occurs. Immunometabolic shifts toward glycolysis are prominent in autoimmune and inflammatory diseases and have been described recently in stress-related psychiatric disorders, including depression (17). Blocking signaling pathways that support this metabolic shift has become an intriguing new target for drug development for the treatment of autoimmune and inflammatory disorders (15, 16). Interestingly, five of the 10 risk genes shared by stress-related disorders and autoimmune disease identified in the study by Zeng et al. play a role in cellular metabolism; the majority of these genes are linked to glycolysis, including EMP2, MYCBP, RRAGC, and SAMSN1, through their involvement with hypoxia-inducible factor-1 alpha, MYC, mammalian target of rapamycin, and AMP-activated protein kinase signaling pathways (16). These data further highlight the relevance of the genetic associations between these two phenotypes and their implications for drug development, especially those linked to immunometabolism. It should be emphasized, however, that any overlap in behavioral and immune phenotypes will be relevant only in a subset of patients with stress-related disorders or PTSD, and therefore the principles of precision psychiatry should apply to drug development in this space. More specifically, clinical trials should use biomarkers to enrich for patients with the relevant immunopathology and assess outcome variables that are directly related to the impact of any treatment on the immune system and ultimately the impact of inflammation on the brain and behavior. In summary, the shared associations between stress-related and immune disorders, genetic and otherwise, provide important clues regarding the role of inflammation in the pathophysiology of these psychiatric conditions, while also shedding light on a path forward for the development of mechanism-based, targeted treatments for these diseases.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (Miller); Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich (Binder).Send correspondence to Dr. Miller ([email protected]).Dr. Miller has served as a consultant for Cerevel Therapeutics and Sirtsei Pharmaceuticals. Dr. Binder reports no financial relationships with commercial interests.REFERENCES1. Sumner JA, Nishimi KM, Koenen KC, et al.: Posttraumatic stress disorder and inflammation: untangling issues of bidirectionality. Biol Psychiatry 2020; 87:885–897Crossref, Medline, Google Scholar2. Katrinli S, Oliveira NCS, Felger JC, et al.: The role of the immune system in posttraumatic stress disorder. Transl Psychiatry 2022; 12:313Crossref, Medline, Google Scholar3. O'Donovan A, Cohen BE, Seal KH, et al.: Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry 2015; 77:365–374Crossref, Medline, Google Scholar4. Miller AH, Raison CL: The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16:22–34Crossref, Medline, Google Scholar5. Passos IC, Vasconcelos-Moreno MP, Costa LG, et al.: Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry 2015; 2:1002–1012Crossref, Medline, Google Scholar6. Dube SR, Fairweather D, Pearson WS, et al.: Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med 2009; 71:243–250Crossref, Medline, Google Scholar7. Zannas AS, Jia M, Hafner K, et al.: Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci U S A 2019; 116:11370–11379Crossref, Medline, Google Scholar8. Eraly SA, Nievergelt CM, Maihofer AX, et al.: Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 2014; 71:423–431Crossref, Medline, Google Scholar9. Zeng Y, Suo C, Yao S, et al.: Genetic associations between stress-related disorders and autoimmune disease. Am J Psychiatry 2023; 180:294–304 Link, Google Scholar10. Seligowski AV, Misganaw B, Duffy LA, et al.: Leveraging large-scale genetics of PTSD and cardiovascular disease to demonstrate robust shared risk and improve risk prediction accuracy. Am J Psychiatry 2022; 179:814–823Link, Google Scholar11. Raison CL, Miller AH: The evolutionary significance of depression in pathogen host defense (PATHOS-D). Mol Psychiatry 2013; 18:15–37Crossref, Medline, Google Scholar12. Raison CL, Rutherford RE, Woolwine BJ, et al.: A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70:31–41Crossref, Medline, Google Scholar13. Davies KA, Cooper E, Voon V, et al.: Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms. Mol Psychiatry 2021; 26:5150–5160Crossref, Medline, Google Scholar14. Kappelmann N, Lewis G, Dantzer R, et al.: Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 2018; 23:335–343Crossref, Medline, Google Scholar15. Pålsson-McDermott EM, O’Neill LAJ: Targeting immunometabolism as an anti-inflammatory strategy. Cell Res 2020; 30:300–314Crossref, Medline, Google Scholar16. O’Neill LAJ, Kishton RJ, Rathmell J: A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16:553–565Crossref, Medline, Google Scholar17. Bekhbat M, Goldsmith DR, Woolwine BJ, et al.: Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming. Mol Psychiatry 2021; 26:7384–7392Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byInsights From Genetic, Neuroimaging, and Behavioral Neuroscience StudiesNed H. Kalin, M.D.1 April 2023 | American Journal of Psychiatry, Vol. 180, No. 4 Volume 180Issue 4 April 01, 2023Pages 259-261 Metrics KeywordsInflammationStressImmune DisordersImmunotargetPosttraumatic Stress Disorder (PTSD)PDF download History Accepted 13 February 2023 Published online 1 April 2023 Published in print 1 April 2023

Journal Digest: CBT With Cardiac Rehab, PMDD Neurochemistry, and More

Back to table of contents Previous article Next article Journal DigestFull AccessJournal Digest: CBT With Cardiac Rehab, PMDD Neurochemistry, and MoreNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:24 Mar 2023https://doi.org/10.1176/appi.pn.2023.04.3.14Antidepressants May Induce Resistance to AntibioticsiStock/SproetniekAntidepressants can induce bacterial resistance to antibiotics, according to a report in PNAS.“While antibiotics are acknowledged as the major driver of increasing antibiotic resistance, little attention is paid to the contribution of antidepressants in this process,” wrote the study authors from the University of Queensland and colleagues.For the study, the researchers exposed E. coli bacteria to five commonly prescribed antidepressants: agomelatine, bupropion, duloxetine, escitalopram, and sertraline—each at five different concentrations (0.1, 1, 10, 50 and 100 mg/ml) for 60 days.After 60 days, exposure to all antidepressants was associated with increased growth of antibiotic-resistant bacteria at significantly faster rates compared with no exposure to antidepressants. Additionally, antibiotic resistance developed faster at higher doses.“Strikingly, the antidepressants sertraline and duloxetine at clinically relevant concentrations in colon (e.g., 50 mg/L) caused an effect after only 1 [day] of exposure,” the authors noted.After examining expression of genes and proteins in these bacteria, the researchers concluded that enhanced production of reactive oxygen molecules following exposure to antidepressants was associated with increased antibiotic resistance.“[O]ur findings highlight the need to re-evaluate the antibiotic-like side effects of antidepressants,” the researchers wrote.Wang Y, Yu Z, Ding P, et al. Antidepressants Can Induce Mutation and Enhance Persistence Toward Multiple Antibiotics. Proc Natl Acad Sci USA. 2023; 120(5): e2208344120. Poor Insight May Increase Risk of Relapse for Psychotic DepressioniStock/FG TradeSome research has shown that people with psychotic depression who have poor insight about their delusions are less likely to achieve depression remission. A report in the Journal of Affective Disorders now suggests such poor insight does not increase the risk of relapse if remission is achieved.Investigators at the University of Toronto and colleagues reviewed data from the STOP-PD II trial, which evaluated the efficacy of a combination of sertraline and olanzapine versus sertraline only for treating psychotic depression in adults. STOP-PD II had three phases: acute, stabilization, and randomized continuation.For the acute phase, adults with psychotic depression received a combination of sertraline (150-200 mg/d) and olanzapine (15-20 mg/d) for up to 12 weeks. Participants who achieved remission (absence of delusions and hallucinations) were then eligible to enroll in an eight-week stabilization phase, where they continued on the same medication regimen. Participants who remained in remission during the stabilization phase were then randomized to continue taking the sertraline-olanzapine combination or switch to sertraline plus placebo; these participants were followed for up to 36 weeks. Patient insight into delusions was assessed at the beginning and end of the stabilization phase.A total of 126 participants entered the final phase of the trial; after 36 weeks, 67 remained in remission, 47 relapsed, and 12 left the study. The investigators found that neither the degree of insight at the start of follow-up nor the change in insight score during the stabilization phase of the trial was associated with relapse risk.“Although unanticipated, this finding can provide reassurance to clinicians that residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression,” the investigators wrote.Song J, Mulsant BH, Sanches M, et al. Residual or Re-emergent Impaired Insight Into Delusions Following Remission is Unrelated to Later Relapse During a Randomized Clinical Trial of Continuation Pharmacotherapy for Psychotic Depression - The STOP-PD II Study. J Affect Disord. 2023; 325: 29-34. Adjunct CBT Can Boost Cardiac Rehabilitation OutcomesiStock/bojanstoryAdding a few sessions of cognitive-behavioral therapy (CBT) to regular cardiac rehabilitation may reduce depression and anxiety symptoms in patients with heart disease. These findings come from a clinical study published in European Heart Journal.For the study, researchers at Bispebjerg and Frederiksberg Hospital in Copenhagen enrolled 147 adults (average age 54) who were recently diagnosed with coronary artery disease or valvular heart disease and were experiencing psychological distress (defined as a score of 8 or higher on the Hospital Anxiety and Depression Scale, or HADS). All participants received eight weeks of cardiac rehabilitation, which consisted of twice weekly exercise sessions along with education about heart disease, managing risk factors, dietary counseling, and more. Half of the participants also received five, two-hour sessions of group CBT delivered by a trained cardiac nurse.After three months, HADS scores (which averaged 17 at baseline) dropped by eight points among the participants who received CBT in combination with cardiac rehabilitation; in the group receiving cardiac rehabilitation only, these scores dropped by four points. The differences between the two groups remained after six months.The adults who received CBT also reported greater improvement in emotional quality of life at six months compared with those receiving cardiac rehabilitation alone. The adults in both groups reported similar physical quality of life.After 12 months, fewer adults receiving CBT were readmitted to a hospital for a cardiovascular issue than those receiving rehabilitation alone (25% vs. 49%, respectively).“Brief group cognitive-behavioral therapy delivered by cardiac nurses may reduce psychological distress and morbidity in the short term, and may be integrated with existing [cardiac rehabilitation] programmes,” the authors concluded.Holdgaard A, Eckhardt-Hansen C, Lassen CF, et al. Cognitive-Behavioural Therapy Reduces Psychological Distress in Younger Patients With Cardiac Disease: A Randomized Trial. Eur Heart J. 2023; 44(11):986-996. Autism Does Not Appear to Accelerate Cognitive AgingiStock/Yaraslau SaulevichGiven the cognitive symptoms associated with autism spectrum disorder (ASD), some researchers have hypothesized that adults with ASD may be prone to accelerated cognitive aging. A longitudinal study appearing in Psychiatry Research now questions this theory.“Even on cognitive domains where autistic adults generally seem to experience more difficulties compared to non-autistic adults (fluency, theory of mind), and on tasks where longitudinal changes were most prominent across groups (response speed, fluency, inhibition, verbal memory) no significant differences in cognitive change between those with and without an autism diagnosis were observed,” wrote the authors from the University of Amsterdam.The study involved adults aged 25 to 85 years, including 128 with ASD and 112 without ASD. These participants received a cognitive test battery multiple times over an average of 3.5 years. The tests assessed 15 different cognitive variables.Although the adults with ASD self-reported more cognitive difficulties at baseline, the researchers found age-related changes in cognition appeared similar in adults with and without ASD.“[D]ifferences in development in various cognitive domains observed in the first stages of life of autistic individuals do not seem to persist or retrace in later stages of life,” the authors wrote. Still, they cautioned that “careful interpretation of the current conclusions is essential, and more longitudinal research is key to understand cognitive decline in older autistic adults precisely, and more generally throughout the autistic population.”Torenvliet C, Groenman AP, Radhoe TA, et al. A Longitudinal Study on Cognitive Aging in Autism. Psychiatry Research. 2023; 321: 115063. PMDD Symptoms May Be Tied to Serotonin UptakeiStock/AndreusA brain imaging study suggests that women with premenstrual dysphoric disorder (PMDD) have more unused serotonin transporters during their premenstrual cycle than women without the disorder. This study, which was published in Biological Psychiatry, also showed that the number of available transporters correlated with the severity of depressive symptoms in the women with PMDD.Investigators at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany, and colleagues conducted PET scans of 30 women with PMDD and 29 matched women without this disorder. All participants were scanned during both their premenstrual phase and preceding periovulatory phase and they completed mood and irritability assessments shortly before each scan.During periovulation, both groups of women showed similar levels of occupied versus available serotonin transporters in the midbrain. During the premenstrual phase, however, the number of available serotonin transporters increased by 18% in women with PMDD (indicating less serotonin movement across neural synapses) while it decreased by 10% in women without PMDD. Women with PMDD who experienced the greatest changes in serotonin transporter availability between the premenstrual and periovulatory phases also reported the greatest increases in depressive symptoms. There was no association between transporter availability and irritability scores.“These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients,” the authors wrote. “These neurochemical findings argue for systematic testing of presymptom-onset dosing of selective serotonin reuptake inhibitors or non-pharmacological strategies to augment extracellular serotonin in PMDD.”Sacher J, Zsido RG, Barth C, et al. Increase in Serotonin Transporter Binding in Patients with Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand PET Imaging Study. Biol Psychiatry. January 18, 2023. Online ahead of print. Psychotrauma Screen Trauma Screen Adapted for Use in IraniStock/FatCameraTrauma is a global issue and a public health concern. A multinational team led by investigators at Iran’s Kermanshah University of Medical Sciences has created and tested a Persian version of the Global Psychotrauma Screen (GPS)—a brief self-report instrument that screens for a range of trauma-related psychological symptoms.The GPS is a 22-item yes/no screen that assesses symptoms of posttraumatic stress disorder (PTSD), depression, anxiety, sleep problems, and dissociation, as well as risk and protective factors.“Kermanshah city, located in the western part of Iran, has experienced multiple wars over the past eight years, involving both airstrikes and ground battles. The area is also one of the most earthquake-prone areas of the world,” the investigators wrote in BMC Psychiatry. “Although several [PTSD] instruments exist in Iran, there is no brief screening tool available that assesses the wide range of psychological reactions to a potentially traumatic event.”The team first constructed a Persian-language version of the GPS with the aid of psychotrauma experts and 30 lay volunteers. The proposed screen was then tested alongside the PTSD Checklist for DSM-5 (PCL-5) and the General Health Questionnaire (GHQ) in 800 adults who had lived through the 2017 Kermanshah earthquake.A comparison of the three assessments suggested that the Persian GPS was consistent and reliable at measuring participants’ trauma symptoms, and that a score above nine suggests a possible PTSD diagnosis. They also found that 52% of the respondents scored above nine, highlighting the high degree of trauma in the region. ■Salimi Y, Hoeboer C, Motevalli Haghi SA, et al. Trauma and its Consequences in Iran: Cross-Cultural Adaption and Validation of the Global Psychotrauma Screen in a Representative Sample. BMC Psychiatry. 2023; 23(1): 65. ISSUES NewArchived

Lifting the cloche: Jeroen Bakkers interviews Didier Stainier.

Didier Stainier is Director of the Department of Developmental Genetics at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany. He became acquainted with the zebrafish model as a PhD student in Walter Gilbert's lab at Harvard, which motivated him to champion the use of this powerful model organism to study heart development as a postdoctoral fellow with Mark Fishman at Massachusetts General Hospital. Although his scientific focus has expanded significantly since then, zebrafish modelling and heart development and regeneration remain key topics in his research. The developmental biology and zebrafish modelling communities have embraced him as an inspiring mentor and advocate for basic research. Jeroen Bakkers is a group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and Professor of Molecular Cardiogenetics at the University Medical Center Utrecht, The Netherlands. Jeroen did hid PhD with Herman Spaink at Leiden University, The Netherlands. A short visit to Massachusetts Institute of Technology during his doctoral training introduced him to the zebrafish model, which he applied to his PhD project. Zebrafish development remained the focus of his career, including during his postdoctoral training in the lab of Matthias Hammerschmidt at the Max Planck Institute of Immunology and Epigenetics in Freiburg and in his own lab at the Hubrecht Institute, where his group uses this powerful model organism to investigate cardiac development, disease and regeneration. Jeroen and Didier met up at a recent conference to talk about their shared interest in cardiac regeneration, a zebrafish mutant with a curious name and Didier's commitment to mentorship.

Evidence and experiment: Curating contexts of Anthropocene geology

Together with research teams from around the world, the Anthropocene Working Group (AWG) has been meticulously quantifying and scrutinizing the global stratigraphic imprint of human activities, the results of which are gathered in this thematic collection of papers in The Anthropocene Review. How can such empirical research, which so impressively articulates the end of a relatively stable Earth System in the mid-20th century, inform our ways of understanding and responding to the planetary crisis that the geological samples quietly represent? In this afterword to the collection we report and reflect on the joint undertaking of the AWG, Haus der Kulturen der Welt and the Max Planck Institute for the History of Science to bring geoscientific evidence, cultural experimentation and historical contextualization together in a shared public framework.

Cluster Preface: Chemical Synthesis and Catalysis in India

Debabrata Maiti (left) received his Ph.D. from Johns Hopkins University in 2008 under the supervision of Prof. Kenneth D. Karlin. After postdoctoral studies at MIT with Prof. Stephen L. Buchwald, he joined the Department of Chemistry at IIT Bombay in 2011. His research interests are focused on the development of new and sustainable synthetic and catalytic methodologies. He is currently an Associate Editor of the ­Journal of Organic Chemistry. Santanu Mukherjee (right) obtained his Ph.D. in 2006, working under the supervision of Prof. Albrecht Berkessel at the Universität zu Köln, Germany. He subsequently worked as a postdoctoral fellow with Prof. Benjamin List at the Max-Planck Institut für Kohlenforschung, and with Prof. E. J. Corey at Harvard University. In 2010, he joined the Department of Organic Chemistry at IISc Bangalore. His research interests revolve around various aspects of asymmetric catalysis, with particular emphasis on organocatalytic enantioselective desymmetrization and transition-metal-catalyzed enantioselective allylic, allenylic and propargylic substitution reactions. He is an Associate Editor of Organic &amp; ­Biomolecular Chemistry.

Sensitivity of MPI-ESM Sea Level Projections to Its Ocean Spatial Resolution

Abstract The dependence of future regional sea level changes on ocean model resolution is investigated based on Max Planck Institute Earth System Model (MPI-ESM) simulations with varying spatial resolution, ranging from low resolution (LR), high resolution (HR), to eddy-rich (ER) resolution. Each run was driven by the shared socioeconomic pathway (SSP) 5-8.5 (fossil-fueled development) forcing. For each run the dynamic sea level (DSL) changes are evaluated by comparing the time mean of the SSP5-8.5 climate change scenario for the years 2080–99 to the time mean of the historical simulation for the years 1995–2014. Respective results indicate that each run reproduces previously identified large-scale DSL change patterns. However, substantial sensitivity of the projected DSL changes can be found on a regional to local scale with respect to model resolution. In comparison to models with parameterized eddies (HR and LR), enhanced sea level changes are found in the North Atlantic subtropical region, the Kuroshio region, and the Arctic Ocean in the model version capturing mesoscale processes (ER). Smaller yet still significant sea level changes can be found in the Southern Ocean and the North Atlantic subpolar region. These sea level changes are associated with changes in the regional circulation. Our study suggests that low-resolution sea level projections should be interpreted with care in regions where major differences are revealed here, particularly in eddy active regions such as the Kuroshio, Antarctic Circumpolar Current, Gulf Stream, and East Australian Current. Significance Statement Sea level change is expected to be more realistic when mesoscale processes are explicitly resolved in climate models. However, century-long simulations with eddy-resolving models are computationally expensive. Therefore, current sea level projections are based on climate models in which ocean eddies are parameterized. The representation of sea level by these models considerably differs from actual observations, particularly in the eddy-rich regions such as the Southern Ocean and the western boundary currents, implying erroneous ocean circulation that affects the sea level projections. Taking this into account, we review the sea level change pattern in a climate model with featuring an eddy-rich ocean model and compare the results to state-of-the-art coarser-resolution versions of the same model. We found substantial DSL differences in the global ocean between the different resolutions. Relatively small-scale ocean eddies can hence have profound large-scale effects on the projected sea level which may affect our understanding of future sea level change as well as the planning of future investments to adapt to climate change around the world.

Meet the First Authors.

HomeCirculation ResearchVol. 132, No. 5Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published2 Mar 2023https://doi.org/10.1161/RES.0000000000000601Circulation Research. 2023;132:542–544is related toMyocardial Milieu Favors Local Differentiation of Regulatory T CellsSlower Calcium Handling Balances Faster Cross-Bridge Cycling in Human MYBPC3 HCMDysregulated Smooth Muscle Cell BMPR2–ARRB2 Axis Causes Pulmonary HypertensionInhibition of Fap Promotes Cardiac Repair by Stabilizing BNPDeacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathyis related toChemogenetics for Gene Therapy Based Targeted Cardiac Electrophysiological ModulationCOVID19 Impairs Cardiac Function via Endothelial H19 and IL6 SignalingAltered Smooth Muscle BMPR2-ARRB2 Axis in PAH (p 545)Download figureDownload PowerPointDr Lingli Wang earned her MD from the Fourth Army Medical University in Xi’an, China, and completed postdoctoral training at Stanford University, before joining the Rabinovitch lab, where she has been a Research Scientist for the past 14 years. In addition to managing the lab and genotyping and phenotyping the extensive transgenic mouse colonies, Dr. Wang has pursued her own research project, investigating how a genetic mutation subverts smooth muscle cell function in pulmonary arterial hypertension. Lingli encourages lab members by reassuring them that, “continuous effort will lead to success”. Outside the lab, she enjoys cooking for her family and jogging.Deep Phenotyping Heart-Specific Tregs (p 565)Download figureDownload PowerPointDr Murilo Delgobo is a postdoctoral researcher at the Comprehensive Heart Failure Center Wuerzburg, Germany. In 2018, he completed his PhD at the Federal University of Santa Catarina, Brazil (Supervisor: Dr. Andre Bafica), studying how host-pathogen interactions shape hematopoiesis. In 2018, he joined Dr. Gustavo Ramos’ Immunocardiology lab, where his research shifted into investigating how T cells differentiate in the infarcted myocardium and how their activity affects tissue repair. His long-term goals are to find new ways to attenuate myocardial diseases by targeting immunological mechanisms and to establish his own cardioimmunology research group. Outside the lab, he enjoys cycling, traveling, and spending time with his family.Inhibition of Fap Promotes Cardiac Repair after MI (p 586)Download figureDownload PowerPointDr. Yuxi Sun is a resident in the Department of Cardiovascular Disease at Xinhua Hospital, affiliated to Shanghai Jiaotong University School of Medicine. He earned his MD/PhD from Tongji University in Internal Medicine (Cardiology). During his doctoral training, he joined Dr. Rui Yue’s lab, where he explored the molecular mechanisms by which cardiac fibroblasts enhance recovery of myocardial infarction. Currently, Dr. Sun continues to focus on cardiac remodeling and heart failure. He hopes to decipher disease-related cellular heterogeneity of cardiac fibroblasts and identify more molecular targets to develop novel and effective drugs with translational potentials.Download figureDownload PowerPointMengqiu Ma is an MD/PhD candidate at Tongji University, Shanghai, China. Mengqiu earned her BS in Medicine and is currently a visiting PhD student at the Max Planck Institute for Heart and Lung Research, Germany. Hoping to find new therapies for patients suffering from heart failure, her focus includes cardiomyocyte regeneration and stem cell therapy. After four years of fruitful research experience under the supervision of Dr. Rui Yue, Mengqiu developed a high sense of responsibility towards unraveling scientific mysteries. Mengqiu would like to become a professor with an independent research group in the future.SIRT2 Deacetylation of Septin4 in Hypertensive CKD (p 601)Download figureDownload PowerPointDr Ying Zhang is a professor and doctoral supervisor at the First Hospital of China Medical University (CMU). She earned a PhD in cell biology from CMU in 2018. Recently, she has acquired multiple Natural Science Foundations of China awards, and as the first or corresponding author published 16 manuscripts including in Circulation Research and Science Advances. Dr. Zhang’s long-term focus on PTM in cardiovascular-related diseases provides theoretical bases for targeted therapy. Her enthusiasm and passion for truth in scientific research has helped her overcome many difficulties and are the factors she attributes to her success.Download figureDownload PowerPointDr Naijin Zhang is a professor and doctoral supervisor at the first hospital of China Medical University (CMU). He earned his PhD from CMU in 2018. Dr. Zhang is a recipient of the National Postdoctoral Innovation Talent Support Program and his research focuses on protein post-translational modifications in cardiovascular diseases for providing theoretical basis and practical value. In recent years, Dr. Zhang, has published 31 manuscripts in Circulation Research, Cell Death Differ, and Redox Biology, among others.The MYBPC3:c772G>A Founder Mutation Causing HCM (p 628)Download figureDownload PowerPointDr Josè Manuel Pioner is a physiologist at the University of Florence working on the mechanisms underlying genetic myopathies and cardiomyopathies. He has acquired skills on human cardiac muscle/cell and myofibril mechanical measurements, which he applies to hiPSC–cardiomyocytes. As a postdoctoral fellow he contributed to the investigation of the (HCM)-MYBPC3:c772G>A variant that started about 10 years ago in the Florence laboratories. In his free time, he often finds new hobbies but playing football and watching his team are still one of his favorites. He loves food tasting and cooking. He believes that creativity and teamwork are the best ingredients for growing his research.Cardiac Chemogenetics (p 645)Download figureDownload PowerPointYehuda Wexler earned a dual BS in biomedical engineering and medical science from the Technion Israel Institute of Science in 2019. Currently, he is part of the MD-PhD program at the Technion’s Rappaport Faculty of Medicine under the supervision of Dr Lior Gepstein. His research is focused on genetic engineering of human pluripotent stem cells and on the development of novel genetic strategies for cardiologic research and therapies. Outside the lab, Yehuda enjoys reading, playing piano, and spending quality time with friends, family, and his supportive wife.COVID19 Impairs Heart Function via lncRNA H19 (p 648)Download figureDownload PowerPointDr. Rio Juni is a postdoctoral fellow in the Physiology Department, Amsterdam UMC. After completing his medical training at the University of Gadjah Mada, Indonesia, he moved to the Netherlands to pursue his interest in cardiovascular research. He completed his research master at CARIM School for Cardiovascular Disease and was awarded a PhD for his work on microRNAs as regulators of cardiac vascular remodeling. Rio’s research interest is endothelial-cardiomyocyte crosstalk in heart pathologies, in particular Heart Failure with Preserved Ejection Fraction (HFpEF). As a postdoctoral fellow in Dr. Reinier Boon’s lab, Rio’s investigating endothelial-related mechanism of HFpEF with focus on lncRNAs. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMyocardial Milieu Favors Local Differentiation of Regulatory T CellsMurilo Delgobo, et al. Circulation Research. 2023;132:565-582Chemogenetics for Gene Therapy Based Targeted Cardiac Electrophysiological ModulationYehuda Wexler, et al. Circulation Research. 2023;132:645-647Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human MYBPC3 HCMJosè Manuel Pioner, et al. Circulation Research. 2023;132:628-644Dysregulated Smooth Muscle Cell BMPR2–ARRB2 Axis Causes Pulmonary HypertensionLingli Wang, et al. Circulation Research. 2023;132:545-564Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNPYuxi Sun, et al. Circulation Research. 2023;132:586-600COVID19 Impairs Cardiac Function via Endothelial H19 and IL6 SignalingRio P. Juni, et al. Circulation Research. 2023;132:648-651Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive NephropathyYing Zhang, et al. Circulation Research. 2023;132:601-624 March 3, 2023Vol 132, Issue 5 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000601PMID: 36862814 Originally publishedMarch 2, 2023 PDF download Advertisement

Abstract P2-17-04: Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis

Abstract Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis Benson C. Selvanesan1,2, Sheelu Varghese1,2, Justyna Andrys5, Ricardo H. Arriaza6, Rahul Prakash6, Purushottam B Tiwari7, Cara Olsen8, Daniel Hupalo2,4, Yuriy Gusev5, Megha N. Patel6, Sara Contente1, Miloslav Sanda9, Aykut Uren7, Matthew D. Wilkerson3,4, Clifton L. Dalgard3,4, Linda S. Shimizu6, Maksymilian Chruszcz6, Tomasz Borowski5, Geeta Upadhyay 1,3,7. Affiliations 1 Department of Pathology, 2 Henry M. Jackson Foundation, 3 Murtha Cancer Center, 4 Department of Anatomy, Physiology, and Genetics 8 Department of Preventive Medicine and Biostatistics Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 5 Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, Cracow, Poland. 6 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA. 7 Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. 9 Max Planck Institute for Heart and Lung Research, Ludwigstrasse, 43, 61231 Bad Nauheim, Germany. Correspond Disclaimer The opinions expressed herein are those of the authors and are not necessarily representative of the official policies of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DOD), the United States Army/Navy/Air Force, the U.S. Government, or any other funding agencies Conflict of Interest None Acknowledgments NIH, NCI, R01 CA227694. NIH, NCI, R21CA256424. DOD, USUHS, VPR-NFP-74-9824. Biomedical Instrumentation Center, USUHS. The American Genome Center, USUHS. Antibody Characterization Program, Clinical Proteomics Tumor Analysis Consortium (CPTAC), National Cancer Institute, National Institute of Health. The Polish Grid Infrastructure, Cracow, Poland. NIH P30CA51008 and 1S10OD019982-01 to Biacore Molecular Interaction Shared Resource (BMISR), Georgetown University. ABSTRACT Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including triple-negative and estrogen receptor-positive breast, ovarian, gastric, head and neck, neuroblastoma, bladder, and lung cancers. Inhibition of LY6K signaling is an ideal therapeutic approach for cancer, since the LY6K protein is not involved in vital organ function. Previously, we identified the small molecule NSC243928 as a binder of LY6K using surface plasmon resonance screening and showed that its activity was dependent on LY6K expression in triple-negative breast cancer cells. Here, we demonstrate the structural basis of the molecular interaction of NSC243928 with LY6K protein and the subsequent inhibition of LY6K function in mitosis and cell division via Aurora B-histone pathway. We observed that LY6K interacts with phosphorylated histones and Aurora B kinases during mitosis and that this interaction was disrupted in the presence of NSC243928. Disruption of LY6K function in mitosis/cytokinesis leads to DNA damage, senescence, and apoptosis of cancer cells. We observed that NSC243928 led to increased binding of LY6K to phosphorylated gammaH2X at S139, which was dependent on NSC243928 interaction with LY6K on phenylalanine 79. Furthermore, we observed increased levels of phosphorylated gammaH2X at S139 and increased caspase-3 activation in the tumor isografts of 4T1 and E0771 mammary tumors treated with NSC243928. These data reveal that LY6K is a novel cell cycle target for therapeutic development in triple-negative breast cancer and other solid cancers with high expression of LY6K, such as bladder cancer, head and neck, and lung cancer. Citation Format: Benson Selvanesan, Sheelu Varghese, Justyna Andrys, Ricardo Arriaza, Rahul Prakash, Purushottam Tiwari, Cara Olsen, Daniel Huplo, yuriy Gusev, Megha Patel, Sara Contente, Miloslav Sanda, Matthew Wilkerson, Clifton Dalgard, Linda S. Shimizu, Maksymilian Chruszcz, Tomasz Borowski, Geeta Upadhyay. Pharmacological inhibition of LY6K induced cell cycle arrest and DNA damage by disrupting the LY6K-Histone-Aurora B signaling axis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-04.

The 2022 nobel prize in physiology or medicine awarded for the decoding of the complete ancient human genome

Since the publication of the first ancient DNA sequence in 1984, experimental methods used to recover ancient DNA have advanced greatly, illuminating previously unknown branches of the human family tree and opening up several promising new avenues for future studies of human evolution. The 2022 Nobel Prize in Physiology or Medicine was awarded to Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, for his work on ancient DNA and human evolution. On his first day back at work, he was thrown in the pond as part of his institute's tradition of celebrating award winners.

Climatic and societal impacts in Scandinavia following the 536 and 540 CE volcanic double event

Abstract. In the Northern Hemisphere, the mid-6th century was one of the coldest periods of the last 2000 years, which was initiated by volcanic eruptions in 536 and 540 CE. Here, we study the effect of this volcanic double event on the climate and society in Scandinavia with a special focus on southern Norway. Using an ensemble of Max Planck Institute Earth system model transient simulations for 521–680 CE, temperature, precipitation, and atmospheric circulation patterns are analyzed. The simulated cooling magnitude is used as input for a growing degree day (GDD) model setup for three different study areas in southern Norway, representative of typical meteorological and landscape conditions. Pollen from bogs inside these study areas are analyzed at high resolution (1–3 cm sample intervals) to give insights into the validity of the GDD model setup with regard to the volcanic climate impact on the regional scale and to link the different data sets with the archeological records. We find that after the 536 and 540 CE double event, a maximum surface air cooling of up to 3.5 ∘C during the mean growing season is simulated regionally for southern Norway. With a scenario cooling of 3 ∘C, the GDD model indicates crop failures were likely in our northernmost and western study areas, while crops were more likely to mature in the southeastern study area. These results are in agreement with the pollen records from the respective areas. Archeological excavations show, however, a more complex pattern for the three areas with abandonment of farms and severe social impacts but also a continuation of occupation or a mix of those. Finally, we discuss the likely climatic and societal impacts of the 536 and 540 CE volcanic double event by synthesizing the new and available data sets for the whole Scandinavia.

Reconstructions and predictions of the global carbon budget with an emission-driven Earth system model

Abstract. The global carbon budget (GCB) – including fluxes of CO2 between the atmosphere, land, and ocean and its atmospheric growth rate – show large interannual to decadal variations. Reconstructing and predicting the variable GCB is essential for tracing the fate of carbon and understanding the global carbon cycle in a changing climate. We use a novel approach to reconstruct and predict the variations in GCB in the next few years based on our decadal prediction system enhanced with an interactive carbon cycle. By assimilating physical atmospheric and oceanic data products into the Max Planck Institute Earth System Model (MPI-ESM), we are able to reproduce the annual mean historical GCB variations from 1970–2018, with high correlations of 0.75, 0.75, and 0.97 for atmospheric CO2 growth, air–land CO2 fluxes, and air–sea CO2 fluxes, respectively, relative to the assessments from the Global Carbon Project (GCP). Such a fully coupled decadal prediction system, with an interactive carbon cycle, enables the representation of the GCB within a closed Earth system and therefore provides an additional line of evidence for the ongoing assessments of the anthropogenic GCB. Retrospective predictions initialized from the simulation in which physical atmospheric and oceanic data products are assimilated show high confidence in predicting the following year's GCB. The predictive skill is up to 5 years for the air–sea CO2 fluxes, and 2 years for the air–land CO2 fluxes and atmospheric carbon growth rate. This is the first study investigating the GCB variations and predictions with an emission-driven prediction system. Such a system also enables the reconstruction of the past and prediction of the evolution of near-future atmospheric CO2 concentration changes. The Earth system predictions in this study provide valuable inputs for understanding the global carbon cycle and informing climate-relevant policy.

Electrochemical contributions: Hans Wenking (1923–2007)

Hans Wenking (Figure 1) was a German electrical engineer, physicist and inventor who devoted his lifetime to the development of electronic equipment for chemistry and physics, particularly constructing the first potentiostats, which became major parts of modern electrochemical instruments. He was the first who described the basic principles of potentiostats. In 1952, Hans Wenking constructed an electronic amplifier for controlling an oscilloscope using a mirror galvanometer with the signals recorded on photographic paper. This amplifier was later used as a core of a new potentiostat with only a power supplier added. This potentiostat, being an important instrument for electrochemical investigations, was designed by Wenking during his work at the Max Plank Institute in Göttingen, Germany. At that time Hans Wenking was working in a group with Professor Karl Friedrich Bonhoeffer where he was appointed to develop a potentiostat that was needed for electrochemical experiments, particularly, for studying corrosion. Until 1957, Wenking's potentiostat was manufactured only for the internal use of the Max Planck Institute in Göttingen. Later Hans Wenking together with Gerhard Bank established “Elektronische Werkstatt Göttingen” to commercialize the potentiostats. From 1959, the company operated under the name “Gerhard Bank Electronik”. Wenking designed the instruments as a freelance, but the brand “Wenking potentiostat” (Figure 2) soon became a famous trademark. The consequence of the potentiostat development was a rush in the development of electrochemical science. The phenomena of metal passivity could be better explained, including mechanisms of oxide layer formation, and far beyond the materials science. The potentiostat became a standard instrument for most electrochemical investigations, particularly for electroanalytical measurements. Independent of Wenking's work, similar instruments were designed by other companies. Tacussel was one of those companies which came to a similar design as Wenking's potentiostats and started manufacturing potentiostats in France. In the USA, Wenking's potentiostats were leading on the market and became standard instruments in electrochemical labs. Wenking has never published his results in scientific papers. On the other hand, Wenking never concealed the technical details of his instruments. The circuits and layouts designed by him were included in the operation manuals for the instruments, and even in some manuals, a detailed theoretical treatise was given. Wenking's instruments were always state-of-the-art and electrochemists of the 1950s–70s used them for many different applications. In the 1920s–50s many polarographic and later voltammetric (e.g., cyclic voltammetry) measurements were performed using a two-electrode configuration composed of a dropping mercury electrode or any other small working electrode and a counter electrode, also serving as a reference. The two-electrode configuration provided reasonable quality of the electrochemical measurements as long as the working electrode was small, the potential sweep was not fast and the background solution included a high concentration of an electrolyte in an aqueous solution, then providing a small current over small resistance in a liquid phase. In other words, the potential drop in the electrolyte solution was not significant to affect the potential measurement precision, so, the applied voltage was close to the actual potential of the working electrode. However, when the analytical measurements started to be performed in non-aqueous solvents with much higher resistance or/and the potential scan rates were much faster (particularly in cyclic voltammetry), then resulting in larger currents, the potential drop in the liquid phase became significant, thus requiring its compensation. At this time, the standard electrochemical/electroanalytical configuration included a three-electrode configuration with a reference electrode added. The three electrodes, working, counter and reference have operated with a potentiostat having more sophisticated electronic circuitry than previously used two-electrode polarographs. While sometimes the reference electrode is not really needed or difficult to be used, particularly in micro-sized electrochemical cells or in implantable electrochemical devices operating in biological fluids, modern electroanalytical devices have always the circuit allowing their operation with three electrodes. The change of the electrochemical instruments operating with two electrodes to three electrodes, thus operating as potentiostats, occurred in approximately the 1950s when numerous potentiostats became commercially available (Figures 3 and 4); many of them were based on the fundamental design of Hans Wenking. Some of these devices were used for control-potential electrolyzers rather than electroanalytical applications. Notably, the electrolysis was conducted with large area electrodes, thus operated with large currents that required very powerful electrical devices. It should be also mentioned that many polarographs produced in 1950 and later have already included potentiostat electrical circuits. A multipurpose electroanalytical instrument constructed by Lingane (Figure 4a) was operating with various functions, including the potentiostat function maintaining the potential of a working electrode constant during electrolysis, in electrogravimetric analysis of metals, electrolytic separations of metals prior to final determinations by other methods, coulometric analysis, and electrolytic preparations by the controlled potential technique. Electrolysis at constant total applied voltage, or with constant current (i.e., operating in potentiostatic or galvanostatic regimes) was also possible. The author declares that he has no conflict of interest.