Schizofrenia risk from C4 genes

COLOURBOX6916567

“A new study, published in Nature this January, Schizophrenia risk from complex variation of complement component 4links , complement component 4 (C4) genes to schizophrenia. C4 genes are important in the major histocompatibility complex (MHC). C4 was found to mediate synapse elimination (called pruning) in development after birth, in mice. These findings might therefore help to explain the reduced number of synapses in brains of humans with schizophrenia.

(Sekar et al., 2016)

Lynn Marquardt

Regulation of nerve signaling molecules by protein-complex formation

IllustrasjonSadafBlog

Neurotransmitters mediate communication between neurons at specific connection sites referred to as synapses. The catecholamines dopamine and noradrenaline are neurotransmitters that control many brain functions such as decision making, motivation, learning and body movements. Many studies have found a connection between altered levels of these transmitters and several psychiatric and neurological disorders like Parkinson’s disease, ADHD and schizophrenia.

The first enzyme in the biosynthesis of catecholamines is called tyrosine hydroxylase (TH). This enzyme regulates the level of catecholamine production in neurons. The activity of TH is controlled at many different ways, one of which is by phosphorylation. Phosphorylation of enzymes is a common mechanism to regulate their activity in response to signals sensed by the cells. This process is called signal transduction, and different signal transduction pathways can regulate the activity of different enzymes within the cell by reversibly adding a phosphate group to one or more amino acid residue of the enzyme.

In a study that involved researchers in the Neurotargeting- and Biorecognition groups, we present new insight into the regulation of TH by phosphorylation. We describe details of how phosphorylation of TH at a specific site leads to the formation of regulatory protein complexes. We characterized the role of the 14-3-3 protein family in regulating TH. There are seven different 14-3-3 proteins found in humans, but we do not know which one of these are the most active in regulating TH. In our study we compared different 14-3-3 protein types in their binding to and regulation of TH. Our results showed that TH formed complexes with all the 14-3-3 proteins, but there were differences in the potency of enzyme activation. We also compared the 14-3-3 proteins for their ability to control TH phosphorylation homeostasis.

This knowledge will give us more detailed overview over the regulation of the catecholamine biosynthesis that can be used further in understanding of defected neuronal pathways and designing the drugs to overcome these defects.

By Sadaf Ghorbani (PhD student)

Science 2.0: The case against science in biomedicine

As the editor of one of the most prestigious peer-reviewed medical journals in the world (The Lancet) said, “the case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.” 1 This is Science 2.0.

Science 2.0 does not bother with the old phenomena of sane hypotheses, experiments, interpretation of results or reasonable conclusions. Those are the limitations of Science 1.0, which prompted the development of the newer version of Science. Science 2.0 is easy to implement as it has the “advantages” of not being based on facts, the experiments being manipulated to support the conclusions and the time-consuming peer-reviews being omitted. In addition, Science 2.0 is also accepting “statistical fairy-tales” about significance1 and it does not care about negative findings (no matter how informative they may be).Negativedata

Since 2015, we are even able to study human health in space as NASA has selected 10 scientists from 12 Universities to examine how zero-gravity may affect the human body (https://www.nasa.gov/twins-study/about;http://time.com/3843801/space-twins-science-kelly/). The concept of this study is very interesting, but it is based on 1 (one!) twin pair. So, there are 10 scientists and 2 participants. This may be the coolest twin study ever, but, most probably, the least statistically powered one in human history.

Science 2.0 is quite alarming: all of its studies are used to develop drugs/vaccines to supposedly help people, train medical staff, educate students and much more. “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines.”2

“In august 2015, the publisher Springer retracted 64 articles from 10 different subscription journals“3, after editorial checks uncovered peer-review fraud. Since 2012, “more than 250 articles have been retracted because of fake reviews — about 15% of the total number of retractions.”3 And there are also cases of data fabrication (http://retractionwatch.com/2015/06/17/columbia-biologists-deeply-regret-nature-retraction-after-postdoc-faked-74-panels-in-3-papers/).

Peter Higgs, who won the Nobel prize for physics in 2013, has famously said: “I wouldn’t be productive enough for today’s academic system.”4 “He would almost certainly have been sacked had he not been nominated for the Nobel in 1980”4 as the British physicist published less than 10 papers between 1964 and 2013.4 Despite such publication record, the University’s authorities decided to keep employing Peter Higgs, because he “might get a Nobel prize – and if he doesn’t” they “can always get rid of him.”4

So, why is it that “individual scientists, including their most senior leaders, do little to alter a research culture that occasionally veers close to misconduct”?1 “Can bad scientific practices be fixed?”1 “One of the most convincing proposals came from outside the biomedical community. Tony Weidberg is a Professor of Particle Physics at Oxford. Following several high-profile errors, the particle physics community now invests great effort into intensive checking and rechecking of data prior to publication. By filtering results through independent working groups, physicists are encouraged to criticise. Good criticism is rewarded.”1 Could good criticism save the science? Let us know your thoughts in the comments below!

1http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2815%2960696-1.pdf

2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964337/pdf/pmed.1000355.pdf

3http://www.nejm.org/doi/pdf/10.1056/NEJMp1512330

4http://www.theguardian.com/science/2013/dec/06/peter-higgs-boson-academic-system

 

Tetyana Zayats

 

Alternative pharmacological strategies for adult ADHD treatment: a systematic review.

COLOURBOX2839548ADHD is a common (~3.5% in adulthood and ~5% in childhood) childhood onset neuropsychiatric condition, leading to high disability because of the frequent psychiatric co-morbidities such as substance abuse, major depression and learning disabilities. Thus, the treatment of ADHD is of high relevance to our society, especially as untreated ADHD has been linked to unemployment, criminality and suicidal attempts. To date, the most effective pharmacological therapy includes methylphenidate and atomoxetine, chemical compounds that affect dopaminergic and noradrenergic neurotransmission. But it is important to consider and study the alternative drugs as they may provide help in dealing with resistant ADHD symptoms and/or co-morbid conditions. The following article provides comprehensive overview of such alternatives: Alternative pharmacological strategies for adult ADHD treatment: a systematic review. In short, amphetamines, antidepressants and metadoxine may be considered suitable pharmacological treatments for symptoms of ADHD and its co-morbid conditions.

Tetyana Zayats

PhD accomplished: Congratulations Ognjen Bojovic

Picture from UIBs webpage
Picture from UIBs webpage

The 21st and 22nd of January 2016 PhD candidate Ognjen Bojovic from the Neuroscience group defended his thesis ”Spinal sensitization and expression of immediate early genes”. The thesis includes not less than three published papers and it is impressive that it was complete during the time-frame of the 3-year PhD program. Ogi has done a very thorough work and started with defining the spatial and temporal distribution of immediate early proteins (IEGs) in the spinal cord after central sensitization. Using the knowledge from the first study, the effect of chronic opioid treatment and neuropathic pain on IEG expression was investigated. The collected insights from the thesis will give guidelines for future researchers and clinicians interested in nociceptive sensitization and pain modulation. Ogi is a MD and is currently doing his training at Haraldsplass hospital in Bergen.

By Karin Wibrand

Rapport fra konferanse om nanomedisin

Foto: Claude Mansiot
Foto: Claude Mansiot

Ved foten av Alpene i den franske byen Grenoble, ble «European Nanomedicine Meeting» arrangert. Konferansen samlet forskere innen medisin, nanoteknologi, farmasi og biokjemi. De fleste kom fra Europa, men noen var også invitert fra USA. Mange interessante foredrag ble holdt, og temaene spredte seg fra utviklingen av nanomaterialer til kliniske studier av nanoprodukter. Arwyn Jones fortalte om hvordan cellene i kroppen tar opp nanopartikler og hvordan celle-penetrerende peptider (CPP) kan forbedre opptaket slik at legemiddelet, som nanopartiklene bærer på, kan leveres til riktig sted inni cellene.

Foto: Lars Herfindal
Foto: Lars Herfindal

Vi var en gjeng på fire som reiste fra Bergen, Maite Bezem og Fredrik G. Johannessen fra Biogjenkjenning, og presenterte våre prosjekter på poster. Våre postere handlet om biologisk nedbrytbare nanopartikler som brukes til å pakke inn tyrosin hydroksylase, også kalt TH. TH er et enzym og kan beskrives som en molekylær maskin. Kroppen trenger det til å produsere lykkemolekylet dopamin. Dopamin er også et signalstoff som hjernen trenger for å kunne styre kroppens bevegelser. Dopaminnivået kan være påvirket i noen sykdommer, blant annet Parkinsons sykdom og ADHD.

Tekst: Maite (Maria Teresa) Bezem (stipendiat, Biogjenkjenning)

Kan datamodeller hjelpe oss å forstå kompliserte sykdommer?

SciLifeLab1

Foto: Rune Kleppe

Mange psykiske lidelser har en høy arvelig komponent. Man tror likevel at det underliggende genetiske bildet er svært sammensatt, og at mange ulike gener bidrar til økt sårbarhet for å utvikle slike lidelser. Endringer i gener kan gi opphav til proteiner (molekylære maskiner) med nye egenskaper, eller endre nivået av proteinene i cellene. Siden mange ulike proteiner deltar i hver prosess som foregår i cellene, er det likevel ikke alltid enkelt å forutsi om slike endringer vil ha noen innvirkning på prosessene som helhet. For mange cellulære prosesser har man kunnskap om mekanistiske detaljer på hvordan proteinene fungerer. Denne kunnskapen kan brukes til å generere datamodeller av de aktuelle prosessene, noe vi kaller systembiologiske modeller. Slike modeller beskriver matematisk hvordan ulike molekyler samvirker med hverandre i cellen og dermed også hvordan molekylenes egenskaper, eller endring i disse, påvirker prosessen som helhet.

Flere cellulære prosesser anses å være avgjørende for utvikling av psykiatriske lidelser. Dette inkluderer prosesser som fører til dannelse av stabile koblinger mellom ulike nerveceller, prosesser som styrer nervecellers evne til å respondere på stimuli og som styrer deres plastisitet. Plastisitet er molekylære endringer som forsterker eller svekker koblinger mellom nerveceller (synapser) ved at responsmønster og følsomhet blir forandret ut fra tidligere aktivitet i synapsene.

Vi ønsker derfor å undersøke om sårbarhetsgener som deltar i slike nøkkelprosesser, kan forstås bedre i lys av systemmodeller. Vi ønsker å koble sammen slike modeller med genetiske analyser av pasientmateriale for å bedre forstå hvordan endringer i flere gener kan sammen bidra til å utvikle psykiatriske lidelser. Vårt hovedfokus er på ADHD og prosjektet er også støttet av Nasjonalt kompetansesenter for nevroutviklingsforstyrrelser og hypersomnier (NevSom).

I prosjektet samarbeider vi bl.a. med forskningsgruppen til Prof. Jeanette Hellgren Kotaleski ved Karolinska institutet/KTH i Stockholm og nå senhøstes var forsker Rune Kleppe på besøk for å arbeide på prosjektet. Kotaleskis forskningsgruppe er eksperter på datasimuleringer av nervekretser og signalprosesser i nerveceller. Gruppen er lokalisert i Science for Life Laboratory (SciLifeLab) bygningen, rett ved siden av Karolinska Institutet. I SciLifeLab holder også prosjekter som det nasjonale genomics infrastrukturen og det humane proteomikk atlas til.

Av Rune Kleppe

KGJN til stede på medisinstudentenes forskningskonferanse, Frampeik

Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst
Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst

30. oktober til 1. november ble medisinstudentenes årlige forskningskonferanse, Frampeik, avholdt. De fire byene Oslo, Bergen, Trondheim og Tromsø veksler på å avholde arrangementet, og i år var det idylliske Tromsø sin tur.

Elisabet Kvadsheim, forskerlinjestudent ved UiB og medlem av KGJN, deltok på konferansen. Forskerlinjen gir medisinstudenter mulighet til å arbeide i en forskningsgruppe parallelt med studiene, og i år har Kvadsheim fulltidspermisjon for å fokusere på forskningen. Hun undersøker hvordan det autonome (ikke-viljestyrte) nervesystemet fungerer hos barn og ungdom med ADHD og angst, ved bruk av et mål kalt hjerteratevariabilitet.

Frampeik gir medisinstudenter som forsker muligheten til å presentere sine prosjekter. Det var et stort spenn i tematikken – alt fra biomarkører og medikamentutprøving til Kvadsheims forskning på ADHD. Kvadsheim fikk flere spørsmål fra salen etter presentasjonen, som kan tyde på at deltakerne syntes dette er et viktig og interessant forskningsområde.

Daniel Jensen