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Chen HF, Hu B, Horth C, Bareke E, Rosenbaum P, Kwon SY, Sirois J, Weinberg DN, Robison FM, Garcia BA, Lu C, Pastor WA, Majewski J
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H3K36 dimethylation shapes the epigenetic interaction landscape by directing repressive chromatin modifications in embryonic stem cells
GENOME RESEARCH 2022 MAY; 32(5):825-837
Epigenetic modifications on the chromatin do not occur in isolation. Chromatin-associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse embryonic stem cell (mESC) model to describe in detail the relationships within the H3K27-H3K36-DNA methylation subnetwork. In particular, we focus on the major epigenetic reorganization caused by deletion of the histone 3 lysine 36 methyltransferase NSD1, which in mESCs deposits nearly all of the intergenic H3K36me2. Although disturbing the H3K27 and DNA methylation (DNAme) components also affects this network to a certain extent, the removal of H3K36me2 has the most drastic effect on the epigenetic landscape, resulting in full intergenic spread of H3K27me3 and a substantial decrease in DNAme. By profiling DNMT3A and CHH methylation (mCHH), we show that H3K36me2 loss upon Nsd1-KO leads to a massive redistribution of DNMT3A and mCHH away from intergenic regions and toward active gene bodies, suggesting that DNAme reduction is at least in part caused by redistribution of de novo methylation. Additionally, we show that pervasive acetylation of H3K27 is regulated by the interplay of H3K36 and H3K27 methylation. Our analysis highlights the importance of H3K36me2 as a major determinant of the developmental epigenome and provides a framework for further consolidating our knowledge of epigenetic networks.
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Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at root s=13 TeV
PHYSICAL REVIEW D 2022 MAY 20; 105(9):? Article 092007
A search for invisible decays of the Higgs boson produced via vector boson fusion (VBF) has been performed with 101 fb(-1) of proton-proton collisions delivered by the LHC at root s = 13 TeV and collected by the CMS detector in 2017 and 2018. The sensitivity to the VBF production mechanism is enhanced by constructing two analysis categories, one based on missing transverse momentum and a second based on the properties of jets. In addition to control regions with Z and W boson candidate events, a highly populated control region, based on the production of a photon in association with jets, is used to constrain the dominant irreducible background from the invisible decay of a Z boson produced in association with jets. The results of this search arc combined with all previous measurements in the VBF topology, based on data collected in 2012 (at root s = 8 TeV), 2015, and 2016, corresponding to integrated luminosities of 19.7, 2.3, and 36.3 fb(-1), respectively. The observed (expected) upper limit on the invisible branching fraction of the Higgs boson is found to be 0.18 (0.10) at the 95% confidence level, assuming the standard model production cross section. The results are also interpreted in the context of Higgs-portal models.
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Bandyopadhyay H, Hay L, Iashvili I, Kharchilava A, McLean C, Nguyen D, Pekkanen J, Rappoccio S, Williams A, Alverson G, Barberis E, Haddad Y, Han Y, Hortiangtham A, Krishna A, Li J, Lidrych J, Madigan G, Marzocchi B, Morse DM, Nguyen V, Orimoto T, Parker A, Skinnari L, Tishelman-Charny A, Wamorkar T, Wang B, Wisecarver A, Wood D, Bueghly J, Chen Z, Gilbert A, Gunter T, Hahn KA, Liu Y, Odell N, Schmitt MH, Velasco M, Band R, Bucci R, Cremonesi M, Das A, Dev N, Goldouzian R, Hildreth M, Anampa KH, Jessop C, Lannon K, Lawrence J, Loukas N, Lutton D, Mariano J, Marinelli N, Mcalister I, McCauley T, Mcgrady C, Mohrman K, Moore C, Musienko Y, Ruchti R, Townsend A, Wayne M, Zarucki M, Zygala L, Bylsma B, Durkin LS, Francis B, Hill C, Ornelas MN, Wei K, Winer BL, Yates BR, Addesa FM, Bonham B, Das P, Dezoort G, Elmer P, Frankenthal A, Greenberg B, Haubrich N, Higginbotham S, Kalogeropoulos A, Kopp G, Kwan S, Lange D, Marlow D, Mei K, Ojalvo I, Olsen J, Stickland D, Tully C, Norberg S, Bakshi AS, Barnes VE, Chawla R, Das S, Gutay L, Jones M, Jung AW, Kondratyev D, Koshy AM, Liu M, Negro G, Neumeister N, Paspalaki G, Piperov S, Purohit A, Schulte JF, Stojanovic M, Thieman J, Wang F, Xiao R, Xie W, Dolen J, Parashar N, Acosta D, Baty A, Carnahan T, Decaro M, Dildick S, Ecklund KM, Freed S, Gardner P, Geurts FJM, Li W, Padley BP, Redjimi R, Rotter J, Shi W, Leiton AGS, Zhang L, Bodek A, de Barbaro P, Demina R, Dulemba JL, Fallon C, Ferbel T, Galanti M, Garcia-Bellido A, Hindrichs O, Khukhunaishvili A, Ranken E, Taus R, Van Onsem GP, Goulianos K, Chiarito B, Chou JP, Gandrakota A, Gershtein Y, Halkiadakis E, Hart A, Heindl M, Karacheban O, Laflotte I, Lath A, Montalvo R, Nash K, Osherson M, Salur S, Schnetzer S, Somalwar S, Stone R, Thayil SA, Thomas S, Wang H, Acharya H, Delannoy AG, Fiorendi S, Spanier S, Bouhali O, Dalchenko M, Delgado A, Eusebi R, Gilmore J, Huang T, Kamon T, Luo S, Malhotra S, Mueller R, Overton D, Rathjens D, Safonov A, Akchurin N, Damgov J, Hegde V, Lamichhane K, Mengke T, Muthumuni S, Peltola T, Volobouev I, Whitbeck A, Appelt E, Greene S, Gurrola A, Johns W, Melo A, Padeken K, Romeo F, Sheldon P, Tuo S, Velkovska J, Arenton MW, Cardwell B, Cox B, Cummings G, Hakala J, Hirosky R, Joyce M, Ledovskoy A, Li A, Neu C, Lara CEP, Tannenwald B, White S, Poudyal N, Black K, Bose T, Dasu S, De Bruyn I, Everaerts P, Galloni C, He H, Herndon M, Herve A, Hussain U, Lanaro A, Loeliger A, Loveless R, Sreekala JM, Mallampalli A, Mohammadi A, Pinna D, Savin A, Shang V, Smith WH, Teague D, Trembath-Reichert S, Vetens W
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Observation of B-0 ->psi(2S)K-S(0)pi(+)pi(-) and B-s(0)->psi(2S)K-S(0) decays
EUROPEAN PHYSICAL JOURNAL C 2022 MAY 31; 82(5):? Article 499
Using a data sample of root s = 13 TeV protonproton collisions collected by the CMS experiment at the LHC in 2017 and 2018 with an integrated luminosity of 103 fb(-1), the B-s(0) -> psi(2S)K-S(0) and B-0 -> psi(2S)K-S(0) pi(+) pi(-) decays are observed with significances exceeding 5 standard deviations. The resulting branching fraction ratios, measured for the first time, correspond to B(B-s(0) -> psi(2S)K-S(0))/B(B-0 Zeta -> psi(2S)K-S(0)) = (3.33 +/- 0.69(stat) +/- 0.11 (syst) +/- 0.34 (f(s)/f(d))) x 10(-2) and B(B-0 -> psi(2S)K-S(0) pi(+) pi(-))/B(B-0 -> psi(2S)K-S(0)) = 0.480 +/- 0.013 (stat) +/- 0.032 (syst), where the last uncertainty in the first ratio is related to the uncertainty in the ratio of production cross sections of B-s(0) and B-0 mesons, f(s)/f(d).
Azevedo EP, Ivan VJ, Friedman JM, Stern SA
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Higher-Order Inputs Involved in Appetite Control
BIOLOGICAL PSYCHIATRY 2022 MAY 15; 91(10):869-878
The understanding of the neural control of appetite sheds light on the pathogenesis of eating disorders such as anorexia nervosa and obesity. Both diseases are a result of maladaptive eating behaviors (overeating or undereating) and are associated with life-threatening health problems. The fine regulation of appetite involves genetic, physiological, and environmental factors, which are detected and integrated in the brain by specific neuronal populations. For centuries, the hypothalamus has been the center of attention in the scientific community as a key regulator of appetite. The hypothalamus receives and sends axonal projections to several other brain regions that are important for the integration of sensory and emotional information. These connections ensure that appropriate behavioral decisions are made depending on the individual's emotional state and environment. Thus, the mechanisms by which higher-order brain regions integrate exteroceptive information to coordinate feeding is of great importance. In this review, we will focus on the functional and anatomical projections connecting the hypothalamus to the limbic system and higher-order brain centers in the cortex. We will also address the mechanisms by which specific neuronal populations located in higher-order centers regulate appetite and how maladaptive eating behaviors might arise from altered connections among cortical and subcortical areas with the hypothalamus.
Barad DH, Albertini DF, Molinari E, Gleicher N
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IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study
HUMAN REPRODUCTION 2022 MAY 30; 37(6):1194-1206
STUDY QUESTION What are the outcomes for patients who choose to move embryos diagnosed as abnormal by preimplantation genetic testing for aneuploidy (PGT-A) to a new institution for transfer after the diagnosing institution refused to transfer them? SUMMARY ANSWER Many patients seek to have selected embryos with PGT-A abnormal trophectoderm biopsies transferred recognizing that these embryos can still offer a chance of pregnancy and live birth. WHAT IS KNOWN ALREADY : PGT-A is a widely practiced method of selecting embryos for transfer based on biopsy of a few cells. Many clinical practices refuse to transfer PGT-A abnormal embryos even when there are no other 'normal' embryos available. STUDY DESIGN, SIZE, DURATION This is a prospective cohort of 69 couples who, since 2014, moved a total of 444 PGT-A abnormal embryos previously refused transfer at their parent institutions to our practice. Among these, 50 patients have, thus far, undergone 57 transfer cycles of 141 embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS Embryos diagnosed at other institutions by PGT-A as abnormal (mostly using next generation sequencing) were moved to our academically affiliated private fertility and research center in New York City. Female age at retrieval was 41.35 +/- 3.98 years, 74% were Caucasian, 12% Asian and 10% were of African descent. All embryos identified as PGT-A abnormal among prospectively identified couples were recorded in our center's registry. MAIN RESULTS AND THE ROLE OF CHANCE Among the 144 embryos transferred 102 (72.3%) had only 1 or 2 chromosomal abnormalities, 30 (21.3%) had 3 or more and 9 (6.4%) were 'undiagnosed' because of degraded DNA, yet still had been refused transfer. Transfer of PGT-A abnormal embryos resulted in 8 live births, 11 miscarriages and no voluntary terminations. One child was born with a segmental duplication and required repair of coarctation of the aorta as a newborn. Many couples with only PGT-A abnormal embryos are willing to have their PGT-A abnormal embryos transferred and such transfers can result in the establishment of ongoing euploid pregnancies and live births. LIMITATIONS, REASONS FOR CAUTION Findings in this case series represent couples who chose to have their embryos transferred after having been refused transfer elsewhere and may not be representative of the wider population of couples undergoing IVF with PGT-A in general. Not all abnormal phenotypes present in the immediate postnatal period so it will be important to continue to follow the development of these children. WIDER IMPLICATIONS OF THE FINDINGS PGT-A can result in a clinics refusal to transfer embryos with abnormal PGT-A biopsies, even those with mosaic findings, consequently large numbers of infertile women are prematurely advised that their only chance of motherhood is through third-party egg-donation. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by intramural funds from the Center for Human Reproduction and the not-for-profit research Foundation for Reproductive Medicine, both in New York, NY, USA. N.G. and D.H.B. are listed as co-inventors on several U.S. patents. One of these patents (US Patent# 7,615,544) relates to pre-supplementation of hypo-androgenic infertile women with androgens, such as DHEA and testosterone and, therefore, at least peripherally related to the subject of this manuscript. N.G. and D.F.A. also received travel funds and speaker honoraria from several pharmaceutical and medical device companies, though none related to the here presented subject and manuscript. N.G. is a shareholder in Fertility Nutraceuticals and he and D.H.B. receive royalty payments from Fertility Nutraceuticals LLC.
Parrish RH, Ashworth LD, Lobenberg R, Benavides S, Cies JJ, MacArthur RB
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Compounded Nonsterile Preparations and FDA-Approved Commercially Available Liquid Products for Children: A North American Update
PHARMACEUTICS 2022 MAY; 14(5):? Article 1032
The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA)-approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms, and to propose lists of compounded nonsterile preparations (CNSPs) that should be developed as commercially available FDA-approved finished liquid dosage forms, as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and professionals are encouraged to continue to work together to improve the likelihood that patients will receive high-quality standardized extemporaneously compounded CNSPs and US-FDA-approved products.
Manry J, Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Michailidis E, Hoffmann HH, Eto S, Garcia-Prat M, Bizien L, Parra-Martinez A, Yang R, Haljasmagi L, Migaud M, Sarekannu K, Maslovskaja J, de Prost N, Tandjaoui-Lambiotte Y, Luyt CE, Amador-Borrero B, Gaudet A, Poissy J, Morel P, Richard P, Cognasse F, Troya J, Trouillet-Assant S, Belot A, Saker K, Garcon P, Riviere JG, Lagier JC, Gentile S, Rosen LB, Shaw E, Morio T, Tanaka J, Dalmau D, Tharaux PL, Sene D, Stepanian A, Megarbane B, Triantafyllia V, Fekkar A, Heath JR, Franco JL, Anaya JM, Sole-Violan J, Imberti L, Biondi A, Bonfanti P, Castagnoli R, Delmonte OM, Zhang Y, Snow AL, Holland SM, Biggs CM, Moncada-Velez M, Arias AA, Lorenzo L, Boucherit S, Anglicheau D, Planas AM, Haerynck F, Duvlis S, Ozcelik T, Keles S, Bousfiha AA, El Bakkouri J, Ramirez-Santana C, Paul S, Pan-Hammarstrom Q, Hammarstrom L, Dupont A, Kurolap A, Metz CN, Aiuti A, Casari G, Lampasona V, Ciceri F, Barreiros LA, Dominguez-Garrido E, Vidigal M, Zatz M, van de Beek D, Sahanic S, Tancevski I, Stepanovskyy Y, Boyarchuk O, Nukui Y, Tsumura M, Vidaur L, Tangye SG, Burrel S, Duffy D, Quintana-Murci L, Klocperk A, Kann NY, Shcherbina A, Lau YL, Leung D, Coulongeat M, Marlet J, Koning R, Reyes LF, Chauvineau-Grenier A, Venet F, Monneret G, Nussenzweig MC, Arrestier R, Boudhabhay I, Baris-Feldman H, Hagin D, Wauters J, Meyts I, Dyer AH, Kennelly S, Bourkeh NM, Halwan R, Sharif-Askar FS, Dorgham K, Sallette J, Sedkaoui SM, AlKhater S, Rigo-Bonnin R, Morandeira F, Roussel L, Vinh DC, Erikstrup C, Condino-Neto A, Prando C, Bondarenko A, Spaan AN, Gilardin L, Fellay J, Lyonnet S, Bilguvar K, Lifton RP, Mane S, Anderson MS, Boisson B, Beziat V, Zhang SY, Andreakos E, Hermine O, Pujol A, Peterson P, Mogensen TH, Rowen L, Mond J, Debette S, de Lamballerie X, Burdet C, Bouadma L, Zins M, Soler-Palacin P, Colobran R, Gorochov G, Solanich X, Susen S, Martinez-Picado J, Raoult D, Vasse M, Gregersen PK, Piemonti L, Rodriguez-Gallego C, D Notarangelo L, Su HC, Kisand K, Okada S, Puel A, Jouanguy E, Rice CM, Tiberghien P, Zhang Q, Casanova JL, Abel L, Cobat A
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022 MAY 24; 119(21):? Article e2200413119
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-alpha, IFN-omega, and/or IFN-beta are found in similar to 20% of deceased patients across age groups, and in similar to 1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-alpha 2 or IFN-omega, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and >= 70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those >= 80 y old for autoantibodies neutralizing IFN-alpha 2 or IFN-omega, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-alpha 2 and IFN-omega. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
Dean N, Jones R, DaSilva J, Chionchio G, Ng H
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The Mnn10/Anp1-dependent N-linked outer chain glycan is dispensable for Candida albicans cell wall integrity
GENETICS 2022 MAY 5; 221(1):?
Candida albicans cell wall glycoproteins, and in particular their mannose-rich glycans, are important for maintaining cellular integrity as well as host recognition, adhesion, and immunomodulation. The asparagine (N)-linked mannose outer chain of these glycoproteins is produced by Golgi mannosyltransferases (MTases). The outer chain is composed of a linear backbone of similar to 50 alpha 1,6-linked mannoses, which acts as a scaffold for addition of similar to 150 or more mannoses in other linkages. Here, we describe the characterization of C. albicans OCH1, MNN9, VAN1, ANP1, MNN10, and MNN11, which encode the conserved Golgi MTases that sequentially catalyze the alpha 1,6 mannose outer chain backbone. Candida albicans och1 Delta/Delta, mnn9 Delta/Delta, and van1 Delta/Delta mutants block the earliest steps of backbone synthesis and like their Saccharomyces cerevisiae counterparts, have severe cell wall and growth phenotypes. Unexpectedly, and in stark contrast to S. cerevisiae, loss of Anp1, Mnn10, or Mnn11, which together synthesize most of the backbone, have no obvious deleterious phenotypes. These mutants were unaffected in cell morphology, growth, drug sensitivities, hyphal formation, and macrophage recognition. Analyses of secreted glycosylation reporters demonstrated that anp1 Delta/Delta, mnn10 Delta/Delta, and mnn11 Delta/Delta strains accumulate glycoproteins with severely truncated N-glycan chains. This hypo-mannosylation did not elicit increased chitin deposition in the cell wall, which in other yeast and fungi is a key compensatory response to cell wall integrity breaches. Thus, C. albicans has evolved an alternate mechanism to adapt to cell wall weakness when N-linked mannan levels are reduced.
Magnasco MO
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Robustness and Flexibility of Neural Function through Dynamical Criticality
ENTROPY 2022 MAY; 24(5):? Article 591
In theoretical biology, robustness refers to the ability of a biological system to function properly even under perturbation of basic parameters (e.g., temperature or pH), which in mathematical models is reflected in not needing to fine-tune basic parameter constants; flexibility refers to the ability of a system to switch functions or behaviors easily and effortlessly. While there are extensive explorations of the concept of robustness and what it requires mathematically, understanding flexibility has proven more elusive, as well as also elucidating the apparent opposition between what is required mathematically for models to implement either. In this paper we address a number of arguments in theoretical neuroscience showing that both robustness and flexibility can be attained by systems that poise themselves at the onset of a large number of dynamical bifurcations, or dynamical criticality, and how such poising can have a profound influence on integration of information processing and function. Finally, we examine critical map lattices, which are coupled map lattices where the coupling is dynamically critical in the sense of having purely imaginary eigenvalues. We show that these map lattices provide an explicit connection between dynamical criticality in the sense we have used and "edge of chaos" criticality.
Veleanu M, Urrieta-Chavez B, Sigoillot SM, Paul MA, Usardi A, Iyer K, Delagrange M, Doyle JP, Heintz N, Becamel C, Selimi F
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Modified climbing fiber/Purkinje cell synaptic connectivity in the cerebellum of the neonatal phencyclidine model of schizophrenia
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022 MAY 24; 119(21):? Article e2122544119
Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects, and neonatal subchronic administration of PCP in rodents leads to long-term behavioral changes relevant for schizophrenia. The cerebellum is increasingly recognized for its role in diverse cognitive functions. However, little is known about potential cerebellar changes in models of schizophrenia. Here, we analyzed the characteristics of the cerebellum in the neonatal subchronic PCP model. We found that, while the global cerebellar cytoarchitecture and Purkinje cell spontaneous spiking properties are unchanged, climbing fiber/Purkinje cell synaptic connectivity is increased in juvenile mice. Neonatal subchronic administration of PCP is accompanied by increased cFos expression, a marker of neuronal activity, and transient modification of the neuronal surfaceome in the cerebellum. The largest change observed is the overexpression of Ctgf, a gene previously suggested as a biomarker for schizophrenia. This neonatal increase in Ctgf can be reproduced by increasing neuronal activity in the cerebellum during the second postnatal week using chemogenetics. However, it does not lead to increased climbing fiber/Purkinje cell connectivity in juvenile mice, showing the complexity of PCP action. Overall, our study shows that administration of the drug of abuse PCP during the developmental period of intense cerebellar synaptogenesis and circuit remodeling has long-term and specific effects on Purkinje cell connectivity and warrants the search for this type of synaptic changes in psychiatric diseases.