Could dopamine agonists aid in drug development for anorexia nervosa?

Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways

Phosphonated Lower-Molecular-Weight Polyethyleneimines as Oilfield Scale Inhibitors: An Experimental and Theoretical Study

For many years, amino methylenephosphonate (-CH2-N-PO3H2)-based scale inhibitors (SIs) have been deployed for preventing various scales in the oil and gas industry, particularly for squeeze treatment applications. However, this class of phosphonate inhibitors showed several limitations related to environmental concerns and compatibility with brine solutions. The low toxicity of low-molecular-weight polyethyleneimine (LMW-PEI) encouraged us to phosphonate a series of branched and linear PEIs via the Moedritzer–Irani reaction. The phosphonated polyethyleneimine PPEIs are branched PPEI-600, branched PPEI-1200, branched PPEI-2000, and linear PPEI-5000. The newly synthesized PPEIs (branched and linear) were screened for calcium carbonate and barium sulfate utilizing a high-pressure dynamic tube-blocking rig at 100 °C and 80 bar. Moreover, we report the compatibility activity of all PPEIs with various concentrations of calcium ions (up to 10000 ppm). The morphology of the calcium carbonate and barium sulfate scale crystals in the absence and presence of linear PPEI-5000 was also investigated under static conditions using scanning electron microscopy (SEM). The obtained results showed that all branched and linear PPEIs gave moderate calcite and barite inhibition activities. It was also found that all branched PPEIs gave moderate to poor calcium compatibility at high dosages of calcium ions (1000–10 000 ppm). Interestingly, linear PPEI-5000 displayed superior compatibility properties at high dosages of SI (up to 50 000 ppm) and high concentrations of Ca2+ ions (up to 10 000 ppm). Furthermore, field emission scanning electron microscopy analysis confirmed that the crystal shapes of CaCO3 and BaSO4 mineral scales are greatly changed in the presence of linear PPEI-5000. At high dosages of linear PPEI-5000 SI (100 ppm), the CaCO3 crystals are completely converted from cubic-shaped blocks (blank calcite) into long cluster shapes. Density functional theory (DFT) simulations reveal favorable interactions of PPEI polymers with the two mineral facets (calcite and barite) with more affinity toward the calcite surface. PPEI with more phosphonate groups exhibits affinities comparable to the commercial-scale inhibitors. The high density of the phosphonate groups on the branched PPEI and its strong affinity toward calcium ions explain its poor calcium compatibility. The polymer flocculation and sluggish barite kinetics are the potential reasons for its low performance against thepublishedVersio

Momentum-2022

A Journal of Undergraduate Research.https://csuepress.columbusstate.edu/momentum/1008/thumbnail.jp

The Impact of Trauma on Exposure and Response Prevention (Ex/RP) Treatment Outcomes for Obsessive-Compulsive Disorder

Despite the high prevalence of trauma in treatment-seeking individuals with obsessive-compulsive disorder (OCD), the role of trauma in OCD treatment is under-studied. This study examined the relationship between trauma and treatment outcomes using a gold standard intervention for OCD—exposure and response prevention (Ex/RP) therapy. This study also investigated whether inherent traits (intolerance of uncertainty, anxiety sensitivity, emotion regulation, and perfectionism) act as mechanisms of change that mediate the relationship between trauma and Ex/RP treatment outcomes. Using data collected as part of a larger research study, analyses were performed for 76 adult patients with a primary diagnosis of OCD who completed Ex/RP therapy in a naturalistic treatment setting, 28 of whom reported experiencing at least one traumatic life event. Although no inherent traits proposed mediated the relationship between trauma and change in OCD symptom severity, results of the study reveal that both the trauma and non-trauma groups experienced significant reductions in OCD symptom severity from pre- to post-Ex/RP. Moreso, individuals with trauma evidenced a slightly greater reduction compared to their non-trauma counterparts. This study is the first of its kind to look at how individuals with OCD and trauma might respond differentially to Ex/RP therapy compared to their non-trauma counterparts, with consideration for these inherent mechanisms of change. Our findings contribute to the body of literature supporting the use of Ex/RP therapy for OCD while offering new insights into the relationship between trauma and treatment outcomes

USSR Space Life Sciences Digest, issue 6

This is the sixth issue of NASA's USSR Space Life Sciences Digest. It contains abstracts of 54 papers recently published in Russian language periodicals and bound collections and of 10 new Soviet monographs. Selected abstracts are illustrated with figures and tables from the original. Additional features include a table of Soviet EVAs and information about English translations of Soviet materials available to readers. The topics covered in this issue have been identified as relevant to 26 areas of aerospace medicine and space biology. These areas are adaptation, biospherics, body fluids, botany, cardiovascular and respiratory systems, developmental biology, endocrinology, enzymology, exobiology, genetics, habitability and environment effects, health and medical treatment, hematology, human performance, immunology, life support systems, mathematical modeling, metabolism., microbiology, morphology and cytology, musculoskeletal system, neurophysiology, nutrition, perception, personnel selection, psychology, radiobiology, reproductive biology, and space medicine

Improving CNV detection from short-read MPS data in neuromuscular disorders

Neuromuscular disorders (NMD) are highly heterogenic with around 1000 reported different subtypes. Most are genetic in origin, and some 500 genes are currently identified to cause NMDs. Massively parallel sequencing (MPS) approaches have been widely used to increase the cost-effectiveness and diagnostic yield in the work-up of the genetic molecular diagnosis and to speed up the process. Copy number variants (CNVs), deletions and duplications larger than 50 base pairs, explain approximately 10% of the Mendelian disorders. No best practices pipelines have been developed yet for CNV analysis from MPS data. Therefore, the detection and verification of CNV findings has often involved complementary methods, such as array comparative genomic hybridization (array CGH), multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR approaches. Recently, various CNV detection programs have been developed, but for widely different types of designated research settings, which complicates choosing the correct approach for NMDs. These individual programs have generally exhibited less than ideal sensitivity and specificity for CNV detection. Our aim was to develop a comprehensive pipeline for the detection and annotation of CNVs with high accuracy from targeted gene panel sequencing and whole exome sequencing (WES) data of patients with NMDs. Four different CNV analysis programs were chosen for this study: CoNIFER, XHMM, ExomeDepth and CODEX. The targeted gene panel MYOcap includes 349 genes for myopathic disorders and MNDcap 302 genes for neurogenic disorders in their current panel versions. 2359 samples were sequenced with MYOcap, 942 samples with MNDcap and 262 samples with WES. This included for the targeted gene panels 24 positive control samples with previously characterized CNVs and 31 negative control samples with certain genes verified to not have CNVs. A detection sensitivity of 100% and specificity of 100% were reached for these control samples. Previously undetected CNVs from MYOcap or MNDcap sequenced samples were verified as true positive detections in 36 cases with MLPA, PCR or array CGH, and eight CNVs were verified as false positive detections. These and the positive control samples were utilized in validation of a predictive logistic regression model. In silico CNV generation into MYOcap sequenced samples provided 18,677 specific and 3892 unspecific CNV detections to initially train the model. The model was trained to differentiate true positive detections from false positive detections in order to increase the specificity of the CNV detection pipeline. The advantage of using four different CNV detection programs compared to using them individually, or with any other combination, was demonstrated by CNV detection sensitivity from the set of in silico CNVs. The predictive model with variables from all four programs provided the highest sensitivity (96.6%) and specificity (87.5%) for predicting CNV detections correctly, indicating an accuracy of 95.5% (95% CI 87.3–99.1%). The CNV detection pipeline together with the predictive model was validated for WES samples with control samples with 235 previously characterized CNVs. For CNVs spanning at least three exons, the detection sensitivity was 97.3% and the sensitivity of the predicative model was 99.3% after adjusting the model threshold for WES data. The CNV annotation platform cnvScan was expanded to contain the most recent CNV population databases as well as in-house CNV databases for all the sequenced sample sets. CNV detection results were filtered by < 1% frequency with reciprocal overlap of 90% in the common CNV population databases, with both it and < 5% frequency with 50% reciprocal overlap in the in-house CNV database, and by the true positive prediction with the model. These procedures significantly decreased the workload (with 3–13% of the original CNV detections preserved) in evaluating the CNVs further regarding clinical significance. The added value, i.e. the additional diagnostic yield from CNVs for both the targeted gene panel sequenced samples and WES samples was estimated to be 1.9%. Altogether 39 final genetic diagnoses were solved with these CNV findings. In addition, 18 patient cases had a likely pathogenic finding, and five had a heterozygous CNV likely pathogenic for a recessive disease without association to the patient’s phenotype. The clarified cases included six different DMD deletions or duplications causing dystrophinopathies. In three sequenced familial cases, the detected CNVs in CACNA1A, SGCD and TTN genes co-segregated with the disease. One case had two separate genetic diseases, tibial muscular dystrophy (TMD) and BMD, caused by the founder mutation FINmaj in the gene TTN and a deletion in DMD. Some of the solved cases had novel findings: the second ever reported large intragenic deletion in NEB causing dominant disease, and the first CNV, an intragenic deletion, in TIA1 in a patient diagnosed with Welander distal myopathy (WDM). Some of the genes associated with NMDs are challenging to analyze from short-read sequencing data due to homology or repetitive regions. An additional script was thus written to differentiate copy numbers of the highly homologous genes, SMN1 and SMN2. Two SMN1/SMN2 copy number 0/3 control cases were successfully recognized, and five cases were identified with a possible exon 7 conversion in SMN1 and a compatible spinal muscular atrophy phenotype. The latter findings were considered likely pathogenic and are awaiting further validation on the genomic level. Comparison of CNV detections within the in-house CNV database revealed divergences in the CNV detections within the triplicate repetitive region of NEB with potentially clinically significant changes. One array CGH validated change correlated well with the nemaline rod pathology observed in the patient. CNV analysis utilizing MPS data from targeted gene panels and WES samples provided increased diagnostic yield as reported also in other studies on NMDs. Our multi-algorithm and -platform approach decreased the workload in variant analysis and provided more insight into the many difficult to analyze genomic regions involved in NMDs. In the future, whole genome sequencing and long-read sequencing will likely provide higher resolution for CNV detections and reveal an even wider spectrum of structural genomic variants, together with other emerging comprehensive methods, such as optical mapping.Lihastaudit ovat hyvin heterogeenisiä, ja niistä on kuvattu noin tuhat alatyyppiä. Suurin osa on perinnöllisiä tauteja, ja tähän mennessä on tunnistettu noin 500 eri lihastauteja aiheuttavaa geeniä. Massiivista rinnakkaissekvensointia (MPS) on käytetty laajalti perinnöllisten tautien diagnostisen prosessin nopeuttamiseksi, kustannustehokkuuden parantamiseksi ja lopullisen geeniperäisen diagnoosin saavuttamiseksi. Kopiolukumuutokset, yli 50 emäsparin deleetiot tai duplikaatiot, aiheuttavat arviolta 10 % Mendelin mukaisesti periytyvistä taudeista. Kopiolukumuutosten havaitsemiseen sekvensointidatasta ei ole vielä kehitetty yleisesti hyväksyttyjä ja suositeltuja käytänteitä. Kopiolukumuutosten havaitsemiseksi ja varmistamiseksi käytetäänkin usein täydentäviä menetelmiä, kuten vertaileva genominen hybridisaatio sirulla (aCGH), rinnastettu ligaatio-riippuvainen alukemonistus (MLPA) ja kvantitatiivinen PCR. Kopiolukumuutosten havaitsemiseen sekvensointidatasta on kehitetty useita työkaluja vaihtelevissa tutkimusasetelmissa, mikä hankaloittaa oikean lähestymistavan valitsemista lihastaudeille. Yksittäisten ohjelmien on todettu tuottavan usein epätäsmällisiä ja herkkyydeltään vaihtelevia tai riittämättömiä havaintoja. Tämän tutkimuksen tavoitteena oli kehittää kattava menetelmä kopiolukumuutosten havaitsemiseen ja annotointiin suurella tarkkuudella kohdennetun geenipaneelin ja koko eksomin (WES) sekvensointidatasta lihastautipotilailta. Tutkimukseen valittiin neljä kopiolukumuutosanalyysin työkalua: CoNIFER, XHMM, ExomeDepth ja CODEX. Kohdennetuista geenipaneeleista MYOcap kattaa 349 geeniä lihaspainotteisille taudeille ja MNDcap 302 hermopainotteisille taudeille nykyisissä paneeliversioissa. MYOcap:lla sekvensointiin 2359 näytettä, MNDcap:lla 942 ja WES:llä 262. Kohdennetuilla geenipaneeleilla sekvensointiin 24 positiivista kontrollinäytettä, joissa on aiemmin tunnistettu kopiolukumuutos, ja 31 negatiivista kontrollinäytettä, joissa tietyt geenit oli varmistettu kopiolukumuutoksia sisältämättömiksi. Kontrollinäytteille saavutettiin kehittämällämme menetelmällä 100 % havaitsemisherkkyys ja 100 % tarkkuus. MYOcap:lla tai MNDcap:lla sekvensoiduista näytteistä havaituista kopiolukumuutoksista 36 varmistettiin todellisiksi havainnoiksi MLPA:lla, PCR:lla tai aCGH:llä ja kahdeksan varmistettiin vääriksi positiivisiksi. Nämä ja positiiviset kontrollinäytteet sisällytettiin logistiseen regressioon perustuvan tilastollisen mallin validointiin. Erottelumallin kehitysvaiheessa MYOcap-sekvensoituihin näytteisiin tehtiin in silico kopiolukumuutoksia, mikä tuotti 18677 spesifiä ja 3892 ei-spesifiä kopiolukumuutoshavaintoa mallinnukseen. Malli kehitettiin erottelemaan todelliset kopiolukumuutoshavainnot vääristä positiivista havainnoista havaintomenetelmän tarkkuuden lisäämiseksi. Neljän ohjelman havaintojen käyttämisen paremmuus verrattuna ohjelmien käyttämiseen yksittäin tai muilla yhdistelmillä todennettiin in silico kopiolukumuutosten havaitsemisen herkkyyden tuloksilla. Erottelumalli, jossa oli muuttujia kaikilta neljältä ohjelmalta, saavutti korkeimman herkkyyden (96,6 %), täsmällisyyden (87,5 %) ja tarkkuuden 95,5 % (95 % CI 87,3–99,1 %) kopiolukumuutosten erottelulle. Kopiolukumuutoshavaitsemismenetelmä ja erottelumalli validoitiin WES-kontrollinäytteillä, joissa oli 235 aiemmin tunnistettua kopiolukumuutosta. Havaitsemisherkkyys kopiolukumuutoksille, jotka sisältävät vähintään kolme eksonia oli 97,3 %, ja erottelumallin herkkyys oli 99,3 % kunhan mallin arviointiraja oli uudelleensäädetty WES-datalle. Kopiolukumuutosten annotaatiotyökalu cnvScan laajennettiin sisältämään uusimmat kopiolukumuutospopulaatiotietokannat ja talonsisäinen kopiolukumuutostietokanta kaikista sekvensointinäytejoukoista. Alkuperäiset kopiolukumuutoshavainnot neljältä ohjelmalta suodatettiin 1 % enimmäisyleisyyden ja vastavuoroisen 90 % muutoksen kattamisen vaatimuksella yleisissä kopiolukumuutospopulaatiotietokannoissa, tällä sekä 5 % enimmäisyleisyyden ja vastavuoroisen 50 % muutoksen kattamisen vaatimuksella talonsisäisessä tietokannassa, ja lisäksi erottelumallilla todellisiin havaintoihin. Nämä toimenpiteet vähensivät merkittävästi työmäärää kliinisen merkityksen arvioinnille kopiolukumuutoksille säästäen 3–13 % alkuperäisistä havainnoista. Lisääntyneiden diagnoosien määrä kopiolukumuutoshavaintojen myötä sekä kohdennetuilla geenipaneeleilla että WES-sekvensoiduilla näytteillä oli noin 1,9 %. Kopiolukumuutoshavainnoilla saavutettiin 39 lopullista geneettistä diagnoosia potilaille. Lisäksi 18:lla tutkitulla oli todennäköisesti patogeeninen löydös, ja viidellä tutkitulla havaittiin heterotsygoottinen kopiolukumuutos, jonka arvioitiin olevan patogeeninen peittyvästi periytyvän taudin variantti ilman yhteyttä potilaan taudinkuvaan. Selvitettyihin tapauksiin sisältyi kuusi eri DMD-geenissä olevaa deleetiota tai duplikaatiota, jotka aiheuttivat dystrofinopatioita. Kolme potilasta, joilla oli oireisia perheenjäseniä, sekvensointiin perhetapauksina, ja havaitut kopiolukumuutokset geeneissä CACNA1A, SGCD ja TTN segregoituivat yhdessä taudin kanssa. Yhdellä tutkitulla havaittiin kaksi perinnöllistä tautia, tibiaalinen lihasdystrofia (TMD) ja BMD, joiden aiheuttajina olivat perustajamutaatio FINmaj TTN-geenissä ja deleetio DMD-geenissä. Osalla selvitetyistä tapauksista oli ennen havaitsemattomia löydöksiä: NEB-geenissä toinen koskaan raportoitu iso geeninsisäinen deleetio, joka aiheuttaa vallitsevasti periytyvän taudin, sekä TIA1-geenin geeninsisäinen deleetio, joka on ensimmäinen havaittu kopiolukumuutos TIA1:ssä Welanderin distaalimyopatiaa (WDM) sairastavalla potilaalla. Jotkin geeneistä, jotka on liitetty lihastauteihin, ovat haastavia analysoitavia lyhytlukuisesta sekvensointidatasta homologian ja toistojaksojen takia. Hyvin homologisille geeneille SMN1 ja SMN2 kehitettiin erillinen ohjelma erottelemaan geenien kopiolukumäärät. Kaksi kontrollitapausta tunnistettiin onnistuneesti SMN1 ja SMN2 kopiolukumäärillä 0 ja 3, ja lisäksi tunnistettiin viisi tapausta, joilla on mahdollisesti eksonin 7 konversio SMN1:ssä ja yhteensopiva spinaalinen lihasatrofia. Jälkimmäiset löydökset luokiteltiin todennäköisesti patogeeniseksi, ja ne odottavat genomista lisävarmistusta. Kopiolukumuutoshavaintojen vertailu NEB-geenin triplikaattitoistoalueella talonsisäisessä tietokannassa paljasti eroavaisuuksia, joilla on potentiaalisesti kliinisesti merkitystä. Yksi aCGH:llä varmistettu muutos korreloi selkeästi nemaliinisauvakappalepatologian kanssa, joka potilaalla oli havaittu. Kopiolukumuutoshavainnointi käyttäen sekvensointidataa kohdennetusta geenipaneelista tai WES-näytteistä lisäsi diagnoosien määrää kuten aiemmissa vastaavissa tutkimuksissa lihastaudeille. Käyttämämme usean algoritmin ja alustan lähestymistapa vähensi varianttianalyysin työmäärää ja tarjosi lisää tietoa useista hankalasti analysoitavista genomisista alueista, jotka on liitetty lihastauteihin. Tulevaisuudessa koko genomin sekvensointi ja pitkälukuinen sekvensointi tarjonnevat paremman resoluution kopiolukumuutoksille ja paljastavat enemmän rakenteellisia genomin muutoksia yhdessä muiden kehitteillä olevien kattavien menetelmien kanssa, kuten optinen kartoitus

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 388)

This bibliography lists 132 reports, articles and other documents introduced into the NASA Scientific and Technical Information Database. Subject coverage includes: aerospace medicine and physiology, life support systems and man/system technology, protective clothing, exobiology and extraterrestrial life, planetary biology, and flight crew behavior and performance