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  • July 18, 2014
  • 06:47 AM

Ultrafine particulate matter air pollution, mice and autism

by Paul Whiteley in Questioning Answers

Reading the headline "Study links air pollution to autism, schizophrenia" in a media piece about the study by Joshua Allen and colleagues* (open-access here) made me want to delve a little more into this research. I've talked before about air pollution and autism (see here) on this blog. Although a healthy degree of scepticism is to be expected with any autism correlation, particularly when it comes to something as generalised as air pollution (or pesticide exposure) there is a growing research interest in how this aspect of the environment may have some bearing on autism risk.Cloudy with a chance of... @ Wikipedia A few details about the Allen study might be useful:This was a study involving mice. I'll repeat that: this was a study involving mice. It involved exposing a particular strain of mouse, modelled to represent a particular age "during early postnatal development" to "human relevant levels" of air pollution in the form of ultrafine particulates (<100 nm).Mouse brains were analysed at different time periods following exposure (24 hours, 40 days and 270 days after) looking at brain morphology, neurotransmitter levels and those all important immune system chemicals involved in processes like inflammation: the cytokines.Results: bearing in mind some quite detailed control of the amount of air pollution exposure mimicking ambient doses near roadways, quite a few effects were noted. There was for example, "a persistent dilation of the lateral ventricles" induced by CAPS (concentrated ambient ultrafine particles) "preferentially in male mice". I believe this is called ventriculomegaly."CAPS induces brain region- and sex-dependent alterations in cytokines and neurotransmitters in both males and females". So in male mice, "increased hippocampal glutamate" among other things was observed. In females, "CAPS reduced hippocampal GABA" and more.Of the various cytokines included for analysis, an old friend ranked up there when it came to some of the results obtained: IL-6. Again, there seemed to be region and sex specific alterations to this cytokine and some of them were "unanticipated" as per the lower levels of IL-6 and other relations in certain areas. IL-6 shares some features of a pro-inflammatory and anti-inflammatory cytokine [2] although more often than not, it is the pro-inflammatory effects which get the headlines [3]. The word 'microglia' also crops up in the Allen results. "CAPS altered IBA-1 immunostaining in the anterior commissure and hippocampus only in males". IBA-1 is a protein expressed in microglia.The authors conclude: "Collectively these data show a dramatic susceptibility of male mice to environmentally relevant levels of early postnatal air pollution exposure, with effects that persist into adulthood and cause permanent neuropathology characterized by ventricular enlargement, a pathology not seen in females".Reiterating again that this was a study of mice and that mice are mice not humans, these are some intriguing data presented by Allen and colleagues. The focus on male mice slots nicely into the [seemingly] over-representation of autism in boys and men. Elevations in glutamate - hippocampal glutamate [4] in male mice - might also overlap with the growing fascination that autism and schizophrenia research have with this neurotransmitter (see here). Some light reading around the finding of "CAPS-induced ventricular enlargement" observed in males leads down some interesting paths such as a possible relationship with agenesis of the corpus callosum [5] reported to be "a major risk factor for developing autism" according to some authors [6]. In short, there are plenty of correlations seemingly heading back to conditions like autism.But... there are a few important points to bear in mind before we get too carried away. First and foremost, nothing is reported in the Allen paper around mouse behaviour and how that may or may not have overlapped with other mouse data trying to model autism. One should always be a little cautious when one hears the words 'autistic behaviour' when it comes to a mouse and whether for example, they vocalise or not, or decide to bury their marbles in a particular way as being representative of facets of the condition. It isn't but it's some of the best animal model behaviour that we currently have including the rat models. Allen et al on this occasion reported nothing about behaviour and how it may or may not link to their physiological findings. Second is a question already asked by someone in/on the Twittersphere: "Air pollution was so much worse many decades ago yet autism rates staggeringly higher today, not then" (thanks Jill). This is an important point which may have lots of different answers bearing in mind your acceptance that things were worse back in olden times (see here for more news from urban China). Perhaps one of the most relevant issues at the moment was the study by Heather Volk and colleagues [7] discussed in a previous post (see here) talking about gene x environment interactions. If one assumes that genes, gene expression, are being affected by air pollution and that some people might already be more 'at risk' than others, there could be something more to do in this area of investigation.Finally, Allen and colleagues seemed to have focused all their attention on the brain of their brave mouse participants. They don't talk about whether other organs or biological systems were affected by air pollution. I know that I'm probably going to get some rolling of the eyes for this but harking back to other mouse models of autism, I note some interest in things like the gastrointestinal (GI) tract to be an upcoming area (see here for example on the VPA mouse model). Assuming that the GI tract will also an important exposure point for air pollution [8], could there be merit in looking at this and other organs too all in the name of the gu... Read more »

  • July 18, 2014
  • 03:00 AM

Intratumoral peripheral small papillary tufts might be a diagnostic clue of BHD

by Lizzie Perdeaux in BHD Research Blog

Contrary to other hereditary kidney cancer conditions, BHD-associated renal tumours are known to be histologically diverse and discordant within families, meaning that members of the same family do not necessarily get the same type of kidney tumour (Pavlovich et al., … Continue reading →... Read more »

Kuroda N, Furuya M, Nagashima Y, Gotohda H, Moritani S, Kawakami F, Imamura Y, Bando Y, Takahashi M, Kanayama HO.... (2014) Intratumoral peripheral small papillary tufts: a diagnostic clue of renal tumors associated with Birt-Hogg-Dubé syndrome. Annals of diagnostic pathology, 18(3), 171-6. PMID: 24767893  

  • July 18, 2014
  • 02:51 AM

Cross-cultural variation in men’s preference for sexual dimorphism in women’s faces

by Farid Pazhoohi in Epistemophil

Both attractiveness judgements and mate preferences vary considerably cross-culturally. We investigated whether men’s preference for femininity in women’s faces varies between 28 countries with diverse health conditions by analysing responses of 1972 heterosexual participants. Although men in all countries preferred feminized over masculinized female faces, we found substantial differences between countries in the magnitude of […]... Read more »

Marcinkowska UM, Kozlov MV, Cai H, Contreras-Garduño J, Dixson BJ, Oana GA, Kaminski G, Li NP, Lyons MT, Onyishi IE.... (2014) Cross-cultural variation in men's preference for sexual dimorphism in women's faces. Biology letters, 10(4), 20130850. PMID: 24789138  

  • July 17, 2014
  • 11:30 PM


by Robb Hollis in Antisense Science

Cancer – the ‘C word’ in far too many of our lives. Wherever you are, it’s unlikely you’ll be able to avoid the news reports and personal stories about people fighting against cancer. Understanding how the disease occurs and how it takes hold over the body is key for developing effective new treatments and managing patients in the clinic, and so huge amounts of money are invested in cancer research every year. But what actually is cancer and how does it develop?... Read more »

Hanahan, D., & Weinberg, R. (2000) The Hallmarks of Cancer. Cell, 100(1), 57-70. DOI: 10.1016/S0092-8674(00)81683-9  

Hanahan D, & Weinberg RA. (2011) Hallmarks of cancer: the next generation. Cell, 144(5), 646-74. PMID: 21376230  

  • July 17, 2014
  • 01:04 PM

A New way to Fight HIV, Using your Genome!

by Gabriel in Lunatic Laboratories

Outsmarting something as “simple” as a virus doesn’t seem like much of a challenge. If only you could set it down to take the SAT’s or something. Unfortunately in the body fighting HIV is more like guerrilla warfare, you take the big losses for a small win. This is no way to wage a war, but HIV is smart. It mutates and sidesteps anything we’ve been able to throw at it. We don’t have a cure, or a vaccine, but we do have scientists trying. New research has made a crucial jump to throwing a curveball at HIV and with it, a possible cure.[…]... Read more »

  • July 17, 2014
  • 02:47 AM

Blood lead levels and childhood behaviour

by Paul Whiteley in Questioning Answers

"Blood lead concentrations, even at a mean concentration of 6.4 µg/dL, were associated with increased risk of behavioral problems in Chinese preschool children, including internalizing and pervasive developmental problems". That was the conclusion of the study by Jianghong Liu and colleagues [1] looking at blood lead levels in preschoolers aged 3-5 years resident in Jiangsu province in China. Some associated media accompanying this study can be viewed here including the text: "This research focused on lower blood lead levels than most other studies and adds more evidence that there is no safe lead level".You lead... @ Wikipedia Lead (Pb) is a metal which has appeared before on this blog - quite a few times in fact (see here and see here for example) - all for the wrong reasons. Outside of it's many and varied industrial uses, including helping many of us get from A to B, lead is pretty dangerous stuff if it manages to find itself into the human and animal body in any amount particularly with its neurotoxic effects [2] in mind.For quite a few years, much of the guidance on exposure to lead had suggested that blood lead levels above 10 μg/dL "should prompt public health actions" [3] albeit not defining "a threshold for the harmful effects of lead". As per that CDC report [3] there has been an increasing realisation that even blood lead levels below 10 microg/dL may have some undesirable effects particularly on infants and young children. Indeed the revised CDC guidance now lists "5 micrograms per deciliter of lead in blood" as the point where concerns should be raised about blood lead levels and action taken.Back to the Liu paper...Looking at spot blood lead levels (BLLs) or even blood lead concentrations for over 1300 youngsters, researchers administered the "Chinese versions of the Child Behavior Checklist and Caregiver-Teacher Report Form" to parents and teachers of participants when children were aged 6 years old.Results: the mean (average) BLL for participants was 6.4 µg/dL, although a range of results were reported. Incremental increases in BLLs correlated with an "increase of teacher-reported behavior scores on emotional reactivity, anxiety problems, and pervasive developmental problems". Also: "mean teacher-reported behavior scores increased with blood lead concentrations, particularly for older girls".The authors conclude: "continued monitoring of blood lead concentrations, as well as clinical assessments of mental behavior during regular pediatric visits, may be warranted".Bearing in mind this was a study looking at parent and teacher scoring of Chinese children and not more formal assessment of behavioural (or cognitive) issues, also focused on spot samples rather than multiple samples to assess BLLs, there are some important lessons to be learned from these results. Not least is the continued undesirability of contact with lead and it's potential effects on behaviour. I think back to some of the chatter on lead exposure and crime (see here) taking into account the old 'correlation is not the same as causation' mantra as one potential societal effect.Reading through some of the other literature in this area, it's not difficult to find supporting information about the detrimental effects of lead exposure particularly in children. The paper by Hou and colleagues [4] (open-access here) pretty much sums it up: "Compared with healthy children, more children with lead poisoning had abnormal behaviors, especially social withdrawal, depression, and atypical body movements, aggressions and destruction". They conclude: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero".Whilst exposure to lead through older formulations of petrol or house paint or plumbing is a declining issue in many areas of the world, I don't think we can be complacent about our situation. Roberts and colleagues [5] commented on this issue in their study (bearing in mind their use of the 10 microg/dL cutoff level). They noted: "Despite a low prevalence of children with EBLL [elevated blood lead levels], parental report suggested that approximately 29% of children had lead-based paint in their home environment". Similar analyses of other areas of lead exposure risk such as dust, soil and water suggest continued monitoring is required as per the study results from Oulhote and colleagues [6].If there is a take-home message from this post and the Liu results it is that lead exposure can have often pronounced developmental effects on behaviour (and cognition) in infants and children and that even markers of low levels of exposure should be examined with much greater assiduity. Without trying to brush everyone with autism as lead poisoned, such results might also direct much greater research attention when findings of EBLL are noted in cases of autism (see here). Indeed, papers like the one from El-Ansary and colleagues [7] might offer much more information than they have hitherto been given credit for...----------[1] Liu J. et al. Blood Lead Concentrations and Children’s Behavioral and Emotional Problems. JAMA Pediatrics. 2014. June 30.[2] Lidsky TI. & Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain. 2003; 126: 5-19.[3] CDC. nterpreting and managing blood lead levels < 10 microg/dL in children and reducing childhood exposures to lead: recommendations of CDC's Advisory Committee on Childhood Lead Poisoning Prevention. MMWR Recomm Rep. 2007 Nov 2;56(RR-8):1-16.[4] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013 Feb 18;10:13.[5] Roberts JR. et al. Are children still at risk for lead poisoning? Clin Pediatr (Phila). 2013 Feb;52(2):125-30.[6] Oulhote Y. et al. mplications of different residential lead standards on children's blood lead levels in France: predictions based on a national cross-sectional survey. Int J Hyg Environ Health. 2013 Nov;216(6):743-50.[7] El-Ansary AK. et al. Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem. 2011 Sep;44(13):1116-20.----------... Read more »

Liu, J., Liu, X., Wang, W., McCauley, L., Pinto-Martin, J., Wang, Y., Li, L., Yan, C., & Rogan, W. (2014) Blood Lead Concentrations and Children’s Behavioral and Emotional Problems. JAMA Pediatrics. DOI: 10.1001/jamapediatrics.2014.332  

  • July 17, 2014
  • 01:00 AM

The DNA of The Price of Darkness

by Bill Sullivan in The 'Scope

Scientists have sequenced the genome of heavy metal pioneer Ozzy Osbourne. Read to find out why and what they found.... Read more »

Sankararaman, S., Mallick, S., Dannemann, M., Prüfer, K., Kelso, J., Pääbo, S., Patterson, N., & Reich, D. (2014) The genomic landscape of Neanderthal ancestry in present-day humans. Nature, 507(7492), 354-357. DOI: 10.1038/nature12961  

  • July 16, 2014
  • 08:17 PM

The Mediterranean Diet and Cognitive Decline

by Gabriel in Lunatic Laboratories

The Mediterranean diet, it may have broad health benefits [let's face it we can't seem to escape the push for it here in the US], but a new study suggests that […]... Read more »

Koyama, A., Houston, D., Simonsick, E., Lee, J., Ayonayon, H., Shahar, D., Rosano, C., Satterfield, S., & Yaffe, K. (2014) Association Between the Mediterranean Diet and Cognitive Decline in a Biracial Population. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. DOI: 10.1093/gerona/glu097  

  • July 16, 2014
  • 03:40 PM

Know your brain: Thalamus

by neurosci in Neuroscientifically Challenged

Where is it?

Thalamus (in red).

The thalamus is a large, symmetrical (meaning there is one in each hemisphere) structure that makes up most of the mass of the diencephalon. A large number of pathways travel through the thalamus, including all of the sensory pathways other than those devoted to olfaction (smell).What is it and what does it do?The thalamus is often described as a relay station. This is because almost all sensory information (with the exception of smell) that proceeds to the cortex first stops in the thalamus before being sent on to its destination. The thalamus is subdivided into a number of nuclei that possess functional specializations for dealing with particular types of information. Sensory information thus travels to the thalamus and is routed to a nucleus tailored to dealing with that type of sensory data. Then, the information is sent from that nucleus to the appropriate area in the cortex where it is further processed.For example, visual information from your retina travels to the lateral geniculate nucleus of the thalamus, which is specialized to handle visual information, before being sent on to the primary visual cortex (the main area for visual processing in the brain). A similar pathway through the thalamus can be delineated for all sensory information except smell. In fact, the majority of all of the signals (not just sensory) that pass to the cortex first pass through the thalamus.Thus, the thalamus has a major role as a gatekeeper for information on its way to the cortex, making sure that the information gets sent to the right place. However, to consider the thalamus as just a gatekeeper or relay station is selling this structure a bit short. A significant portion of the incoming fibers to the thalamus come not from sensory systems, but from the cortex itself. Thus, there are many connections to the thalamus that are involved in taking information from the cortex, modulating it, and then sending it back to the cortex. This means that the thalamus is an important part of cortical processing in general, and more than just a brief stop for signals on their way to the cortex.Thus, it isn't that surprising that the thalamus is involved in complex brain processes like sleep and wakefulness. It even is thought to play a crucial role in maintaining consciousness. So, far from just a relay station, the thalamus is an integral area involved in higher-order brain processing of various types.Sherman, S., & Guillery, R. (2002). The role of the thalamus in the flow of information to the cortex Philosophical Transactions of the Royal Society B: Biological Sciences, 357 (1428), 1695-1708 DOI: 10.1098/rstb.2002.1161... Read more »

Sherman, S., & Guillery, R. (2002) The role of the thalamus in the flow of information to the cortex. Philosophical Transactions of the Royal Society B: Biological Sciences, 357(1428), 1695-1708. DOI: 10.1098/rstb.2002.1161  

  • July 16, 2014
  • 01:01 PM

More Horror from Deepwater Horizon Oil Spill

by Gabriel in Lunatic Laboratories

Deepwater Horizon, it was a technological feat to get oil that deep in the water. Then the spill occurred, when it happened I honestly think more people were in shock […]... Read more »

White, H., Lyons, S., Harrison, S., Findley, D., Liu, Y., & Kujawinski, E. (2014) Long-Term Persistence of Dispersants following the Deepwater Horizon Oil Spill. Environmental Science , 1(7), 295-299. DOI: 10.1021/ez500168r  

  • July 16, 2014
  • 09:37 AM

Video Tip of the Week: VectorBase, for invertebrate vectors of human pathogens

by Mary in OpenHelix

I wish I had been clever enough to coordinate this week’s Video Tip of the Week with “Mosquito Week” a couple of months back. There was a bunch of chatter at that time about this infographic that was released by Bill Gates, which illustrated the contribution of various human-killing species. The mosquito was deemed: The […]... Read more »

Megy K., D. Lawson, D. Campbell, E. Dialynas, D. S. T. Hughes, G. Koscielny, C. Louis, R. M. MacCallum, S. N. Redmond, & A. Sheehan. (2012) VectorBase: improvements to a bioinformatics resource for invertebrate vector genomics. Nucleic Acids Research, 40(D1). DOI:  

  • July 16, 2014
  • 08:05 AM

East To West And Back Again

by Mark Lasbury in As Many Exceptions As Rules

Sunflowers were named by Linnaeus for their round shape and bright color that reminded him of the sun, not because they follow the sun. But they do seem to turn to face the sun each day. A new review has looked at the molecular mechanisms that control the movement of the apex of the plant. But questions remain – how does the plant turn back to the east at night? Why is it that the flower turns but the leaves do not? Why does the movement stop when the flower matures?... Read more »

  • July 16, 2014
  • 04:50 AM

Organic acids as biomarkers of autism?

by Paul Whiteley in Questioning Answers

Whilst I am always a little cautious about the use of the word 'biomarker' when applied to a heterogeneous condition like autism, even the autisms, I am nevertheless always intrigued at any reasonable prospect reported in the scientific literature. So it was when I read the paper by Joanna Kałużna-Czaplińska and colleagues [1] and their assertion that "there is a significant metabolic difference between autistic and non-autistic children" and onwards that "21 metabolites were identified as potential biomarkers".Let me expand on this a little...This was a small study looking at potential biomarker identification on the basis of the analysis of urine samples via gas chromatography-mass spectrometry (GC-MS). If you want some further background on this technique applied to autism research, have a look at a previous post (see here) where it has been utilised. Overnight urine samples from 14 children (aged 4-10 years) diagnosed with an autism spectrum disorder (ASD) undergoing "rehabilition" (whatever that means) were analysed in comparison to samples from 10 asymptomatic controls.Quite a bit of information is included about sample treatment and the analytical method. Each sample result was represented as a TIC (total ion count) and, as is often the case with such methods, data processing was an important part of the analysis. Most compounds were identified by cross-referencing with the NIST mass spectra library and via fragmentation patterns. Principal component analysis (PCA) was "applied to check the dataset structure and assess the variability of the profiles belonging to groups of autistic vs. non-autistic children". Results: as indicated, 21 metabolites were deemed as "potential marker metabolites" some detected in higher quantities in the autism samples, and some lower. Fourteen of these compounds were described as organic acids. Without hopefully breaking any copyright, I've attached a copy of the table included in the paper with all the compounds differing between autism and control samples. The eagle-eyed will also note the big 'H' - homocysteine - to be a part of that list, and as expected, elevations in urinary homocysteine for the autism group as per other work in this area (see here).Given the title of this post I'll point out a few organic acids which seemed to be important differentiators between autism and control samples: (i) levels of beta hydroxybutyric acid were elevated in autism sample. This compounds has been talked about previously on this blog with regards to inborn errors of metabolism and autism (see here). (ii) Hydroxybenzoic acid was again elevated and perhaps ties into other findings from this group [2] potentially indicative of intestinal dysbiosis. (iii) Succinic acid levels were also generally elevated, and as the authors point out: "is considered a potential marker for deficiency of CoQ10 and riboflavin in children with autism". Co-enzyme Q10 y'say? I could go on, but won't.Various statistical models (PCA) were applied to the datasets which led authors to find: "The group of samples from non-autistic control children [were] more homogeneous than the group from autistic children". Further: "There is a clear distinction between those two groups of samples". ROC analysis looking at the performance of the PCA models was also applied leading authors to conclude that there may be something in their results from a diagnostic point of view.Obviously the Kałużna-Czaplińska results are preliminary and in need of further independent replication. I note that quite a bit of the other literature in this area of biomarkers tend to use both training and test sets, where training samples provide your initial compounds of interest and test sets do just that, test your biomarker assumptions (see here). This wasn't the case in the current study but still leaves the door open to independent verification. That also the word 'comorbidity' does not seem to be mentioned as part and parcel of the autism group means the questions of how widespread comorbidity was in the autism participant group and whether this might have exerted an effect on the results obtained are unanswered. I might also quibble about the way that peaks in the TIC were assigned a compound name: "Peaks with the similarity index more than 80% were assigned compound names..." but now I'm just nit-picking.That all being said, I do see some promise in the results obtained by Kałużna-Czaplińska et al. I note in another paper by some of the authors [3] they talk about how probiotic therapy might impact on both some of the behavioural measures of autism and also levels of one of the compounds picked up in their latest analysis, D-arabinitol. Again, I'd like to see more research done on this, alongside their other suggestion on the use of B vitamins (and magnesium) potentially affecting organic acids in cases of paediatric autism [4] talked about in a previous post (see here). The focus on the inner working of the gut, and particularly the trillions of gut bacteria which call us home, potentially being connected to some of these biomarkers, ties in well with an emerging autism research area (see here).Music to close, and yet again my brood provide the inspiration as Bob Marley is fast becoming a YouTube favourite in our home with the classic One Love. You know you're getting old when your kids start listening to cooler music than you do...----------[1] Kałużna-Czaplińska J. et al. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of Chromatography B. 2014. Feb 2.[2] Kałużna-Czaplińska J. Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. Clin Biochem. 2011 Jun;44(8-9):686-91.[3] Kałużna-Czaplińska J. & Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012 Feb;28(2):124-6.[4] Kałużna-Czaplińska J. et al. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children. Nutr Res. 2011 Jul;31(7):497-502.----------... Read more »

  • July 15, 2014
  • 01:30 PM

Schizophrenia and Autism: A New Connection

by Gabriel in Lunatic Laboratories

Autism and Schizophrenia, at first glance there probably isn’t a whole lot in common other than they are disorders that fall in that lovely book the DCM-5. The brain is […]... Read more »

Chie Shimamoto1,, Tetsuo Ohnishi, Motoko Maekawa, Akiko Watanabe, Hisako Ohba, Ryoichi Arai, Yoshimi Iwayama, Yasuko Hisano, Tomoko Toyota, Manabu Toyoshima.... (2014) Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies. Human Molecular Genetics. info:/10.1093/hmg/ddu369

  • July 15, 2014
  • 12:18 PM

Here’s What Happens When You Put Camera Traps in Trees

by Elizabeth Preston in Inkfish

The world holds very few unexplored places between zero and six feet off the ground. If humans can walk right up to it and take a picture, we probably already have. But the tops of the trees, like the bottom of the ocean, are a different story. “We know so much less about arboreal mammal […]The post Here’s What Happens When You Put Camera Traps in Trees appeared first on Inkfish.... Read more »

Gregory, T., Carrasco Rueda, F., Deichmann, J., Kolowski, J., & Alonso, A. (2014) Arboreal camera trapping: taking a proven method to new heights. Methods in Ecology and Evolution, 5(5), 443-451. DOI: 10.1111/2041-210X.12177  

  • July 15, 2014
  • 11:50 AM

Breaking Up is Hard to Do: Photosynthesis, Water-Splitting, and the OEC

by Melissa Chernick in Science Storiented

A very very cool paper was recently published online. The paper details a study that shows the first images of water splitting apart during photosynthesis. So pick you jaw up off the table and we’ll get into the nitty-gritty details. Let’s start by accessing your long-term memory, dragging out some of that basic biology information you buried after high school and grabbing on to that dusty file about photosynthesis. If you remember, plants have little green, bean-shaped energy factories in their cells called chloroplasts. These chloroplasts are filled thylakoids stacked up in grana. The thylakoid membranes contain networks of pigments, including chlorophyll, arranged in aggregates or complexes. Think of them kinda like light energy harvesters. Energy is captured for functional and structural units of protein complexes called Photosystem I (PSI) and Photosystem II (PSII). PSI is the light reaction and converts light energy to chemical energy. The pigments of the complexes each absorb light and then pass along that light energy to the central chlorophyll molecule to do photosynthesis. The energy obtained in this reaction is stored in ATP (adenosine triphosphate) and NADPH (nicotinamide adenine dinucleotide phosphate-oxidase) molecules. PSII, the dark reaction, takes place in the stroma within the chloroplast. This reaction uses the Calvin cycle to convert carbon dioxide and energy from ATP into glucose (sugar). To say that is photosynthesis put shortly and simply would be an understatement, but keep this basic reaction in mind:6 CO2 + 6 H2O à C6H12O6 + 6 O2It is important to mention that in PSII, water is photochemically oxidized to dioxygen (O2) by the oxygen-evolving complex (OEC), a metalloenzyme cluster containing manganese and calcium. The OEC cycles through five photo-catalytic stages (S0-S4) in which four electrons are sequentially extracted from the OEC in four light-driven charge-separation events by a repeatedly photo-oxidized chlorophyll center (Kok cycle). This is the reaction that makes all that oxygen we breathe.2 H2O à S0-S4 à O2 + 4 H+ + 4 e-Photo by: Mary Zhu @ ASUThe new paper by Kupitz et al. (and al. and al. and al.) published in Nature looks closer (very close!) at this PSII water-splitting reaction. They had some issues to overcome if they wanted to collect more information on this reaction, mostly involving the static nature of X-ray crystallography and the damage done to the OEC with this method. Traditional X-ray crystallography enables 1.9Å resolution (near atomic) but the OEC probably suffers X-ray damage. To overcome this, the researchers used serial femtosecond crystallography. This method uses single shot diffraction patterns are collected from a stream of nanocrystals, using 120 Hz femtosecond (one millionth of a nanosecond!!) pulses from an X-ray Free Electron Laser (XFEL). The second is the quality of the structural information. These pulses are so intense that the sample/specimen is destroyed, but the pulse duration is so short that the diffraction is observed before the destruction occurs. The method produces millions of “snapshots” in hours and can collect time-resolved data for dynamic processes like water oxidation in PSII.The researchers developed a multiple-laser illumination scheme to observe this dynamic reaction in thermophilic cyanobacterium (Thermosynechococcus elongates). They progressively excited the OEC in dark-adapted PSII nano/microcrystals by two laser pulses from the dark S1 state via the S2 state to the double-flash putative S3 state (5 and 5.5Å resolution). Believe it or not, that was their method put simply. Essentially, they were able to determine the structures of the states and to produce maps of the protein subunits and cofactors of PSII, including the electron transport chain. They found that PSII undergoes significant conformational changes electron acceptor side and at the Mn4CaO5 core of the OEC. The metal cluster significantly elongates, making room and allowing for binding of the incoming water molecules. Then voilà! Water splitting!So I know what you may be thinking: Why all of that lead-up to a simple protein shape change conclusion? Well, it’s all about mechanism, figuring out the process of photosynthesis at its most basic level. If you think about it, photosynthesis is the biological reaction. It is fundamental to life on Earth as we know it. It converted the oxygen-poor atmosphere of early Earth to the oxygen-rich atmosphere we (and all other respiring organisms) depend on, and continues to supply us with life-giving oxygen. That oxygen comes from this water splitting reaction, and the OEC is one of those structures where you usually have to but "possible model of..." in front. This type of study gives incredible resolution of this structure as well as a new methodology to gain further knowledge. With a more technological viewpoint, work like this could eventually lead to the development of an artificial leaf and synthetic photosynthesis. And, let’s face it, that is really really cool.Kupitz, C., Basu, S.... Read more »

Kupitz, C., Basu, S., Grotjohann, I., Fromme, R., Zatsepin, N., Rendek, K., Hunter, M., Shoeman, R., White, T., Wang, D.... (2014) Serial time-resolved crystallography of photosystem II using a femtosecond X-ray laser. Nature. DOI: 10.1038/nature13453  

  • July 15, 2014
  • 08:00 AM

The Pressure of the World Cup Penalty Kick

by THE 'SCOPE in The 'Scope

Tim Howard was brilliant in goal for the United States at the 2014 World Cup. Flying all over the place, catching, punching, kicking – he looked like he was protecting his family home from post-apocalyptic cannibals. It was very impressive, but the US went out against Belgium 2-1 in extra time, despite Howard’s 17 saves, the most in a single World Cup game in 50 years. Tim Howard had a great game for the US, heck, a great tournament. So great in fact, that Wikipedia temporarily changed the name of the US Secretary of Defense to Tim Howard. The true SOD, Chuck Hagel, called to congratulate Howard. Hagel stated that with some training, Howard could be the real secretary of defense. One, he called after a loss – reminds too many people of Vietnam, and two, what few things does Howard lack to be SOD?In the whole of Team USA’s tournament, Howard didn’t face one penalty kick. This was good for him, since it’s so hard for a goalie to look invincible against a lone player kicking a small ball into a 24 foot (7.3 m) wide goal from only 12 yards (10.9 m) away.In World Cup competition, most penalty kicks are successful, to the tune of about 86%. But penalty kicks come in two flavors, and that percentage only reflects the scoring rate for penalty kicks (PK) that occur during the game. There are also PKs that come when the two teams are still tied after extra time (we Americans call it overtime, but of course we call it soccer too).About 70% of penalty kicks find the back of the net in that situation. Why is there a difference? It’s the same distance, it’s still striker against goalie. The ball is still roughly round with those funny geometric shapes stitched into it. Why does the scoring rate go down so significantly?Billy Joel told us why many years ago – Pressure! The kicker is expected to make the shot – he has such a big advantage. Joe Bag–O-Donuts on his couch is screaming that he could make that shot, and he gets out of breath just opening the chip bag! Let’s investigate how big an advantage the striker actually has, and then we can figure out why it shrinks when it’s time to line up for PKs. Billy Joe’s song has some poignant lines that could apply to penalty kicks. “So far so good but you will come to a place where the only thing you feel are loaded guns in your face and you'll have to deal with pressure.” Or how about, “Don't ask for help you're all alone. Pressure. You'll have to answer to your own pressure.” A good college or professional football player will kick the ball so it reaches a speed of 80 mph (128 kph, or 117 feet per second/35.7 meters per second). At a distance of 12 yards, this means the whole event is over in roughly 0.3 seconds. It takes a goalie about 0.6 seconds to move so that one hand or foot can get to either edge of the goal! You don’t have to be a math magician to see that if the striker can kick the ball on target, it’s going to go in.That’s why most PKs are aimed at the edges of the goal, either up top, in the middle, or on the ground. Most PKs that are missed are aimed up high, so maybe the goalie has a slight advantage there, but still, there’s 192 square feet (17.9 square meters) of space that must be defended in the blink of an eye. Yes, it takes 0.3-0.35 seconds to blink – let’s hope the goalie’s eyes don’t have bad timing.FIFA changed the rule in 1997 so that the goalie can move before the ball is struck, but it doesn’t help that much. He still isn’t allowed to move forward. This would help him narrow the angles and reduce the square footage he has to defend. And if he does move before the ball is kicked, he’s really just guessing. A study of previous World Cups says that goalies only guess correctly about 41% of the time, and guessing right still doesn’t matter if he doesn’t have enough time to get a hand on the ball. ... Read more »

BENJAMIN NOËL and JOHN VAN DER KAMP. (2012) Gaze behaviour during the soccer penalty kick: An investigation of the effects of strategy and anxiety. Int. J. Sport Psychol., 1-20. info:/

  • July 14, 2014
  • 02:48 PM

Can We Grasp The Brain’s Complexity?

by Neuroskeptic in Neuroskeptic_Discover

An entertaining paper just out in Frontiers in Systems Neuroscience offers a panoramic view of the whole of neuroscience: Enlarging the scope: grasping brain complexity The paper is remarkable not just for its content but also for its style. Some examples: How does the brain work? This nagging question is an habitué from the top […]The post Can We Grasp The Brain’s Complexity? appeared first on Neuroskeptic.... Read more »

Tognoli E, & Kelso JA. (2014) Enlarging the scope: grasping brain complexity. Frontiers in systems neuroscience, 122. PMID: 25009476  

  • July 14, 2014
  • 02:27 PM

History of neuroscience: Hodgkin and Huxley

by neurosci in Neuroscientifically Challenged

Hodgkin and Huxley used the large axons of the giant squid to measure voltage changes during an action potential.

By the late 1930s, researchers had come to understand several important things about the conduction of signals within neurons. For example, they knew that signaling within neurons is electrical in nature (as opposed to signaling between neurons, which is usually chemical), and that it occurs in bursts of activity called action potentials. And they knew that action potentials are stimulated by the movement of sodium ions across the neuronal membrane through proteins called ion channels. But the exact details of what is going on during an action potential were not made fully clear until Alan Hodgkin and Andrew Huxley started collaborating on the issue in 1939.What is an action potential?To understand Hodgkin and Huxley's findings, it helps to have some background on what happens during an action potential. When a neuron is at rest, there are a variety of charged particles called ions that are unevenly distributed inside and outside of the cell. Ions are simply atoms that have either gained or lost an electron; this gain or loss of electrons gives the atoms a negative or positive overall charge, respectively. When a neuron isn't excited, positively-charged sodium ions accumulate outside of the neuron, while positively-charged potassium ions accumulate inside. There are also negatively-charged chloride ions and organic ions that accumulate outside and inside the cell, respectively. A number of mechanisms, including both passive (e.g. diffusion) and active (e.g. the Na-K pump) processes, work to create a unequal balance of positively- and negatively-charged particles between the inside and outside of the neuron. This difference in charge is known as the resting membrane potential; typically in neurons it is around -65 to -70 mV, which means that the inside of the neuron is negatively-charged with respect to the outside.During an action potential, the membrane potential rapidly changes. By Hodgkin and Huxley's time it was already suspected that this rapid change was produced by the movement of positively-charged sodium ions from the outside to the inside of a neuron through ion channels. The influx of positively-charged particles was thought to be the basis for the burst of electrical energy that then proceeded to travel down the neuron as an action potential. However, the extent of the change in membrane potential wasn't known, and the exact role of the different types of ions found in the intracellular and extracellular fluid of neurons had yet to be elucidated.Voltage clamps and giant squid axonsOne of the difficulties in understanding action potentials before Hodgkin and Huxley's work was that neurons are incredibly small. (At their largest they are about 100 micrometers, but they can be under 10 micrometers. By comparison, a human hair is about 80 micrometers.) Scientists found that the size of the axons in most species made it difficult or impossible to insert a recording device to measure voltage changes during an action potential.Hodgkin and Huxley got around this problem by studying action potentials in the relatively enormous axons (up to 1 mm in diameter) of the giant squid. They inserted a fine capillary electrode into the giant squid axon and were able to measure electrical changes within the axon during an action potential. They found that the membrane potential of the neuron actually reversed during an action potential, causing the neuron to momentarily have a positive membrane potential. This rapid reversal of membrane potential was the impetus for the generation of the electrical signal underlying the action potential.Hodgkin and Huxley also utilized an innovative tool that allowed them to determine the contribution of different ions to the change in membrane potential seen during an action potential. The device, called a voltage clamp, uses electrical stimulation and feedback to set the membrane potential of a neuron at a particular voltage and keep it there. Previous attempts to gauge the exact contribution of different ions to the action potential were stymied by the voltage-dependency of the ion channels involved. Voltage-dependent ion channels open and close when the membrane potential reaches a particular voltage. Thus, because the action potential involves rapid changes in membrane potential, it also involves rapid fluctuations in the opening and closing of ion channels. This happens so quickly that researchers before Hodgkin and Huxley were unable to slow it down enough to get an understanding of what was going on. By using a voltage clamp, Hodgkin and Huxley essentially were able to "freeze" the neuron at particular voltages, which allowed them to gather details on what was happening in the neuron at each stage in the action potential.Hodgkin and Huxley used the voltage clamp while also manipulating the levels of different ions in the extracellular fluid. In this way they were able to determine the exact contribution of sodium and potassium (and chloride and organic) ions to the action potential. They determined that an influx of sodium ions through voltage-gated sodium ion channels causes a rapid shift in membrane potential, which causes the initiation of the electrical signal that is known as the action potential. Immediately after this change in membrane potential, however, ion channels open that allow potassium ions to flow out of the neuron. This helps the membrane potential to return to its normal level.Hodgkin and Huxley's work for the first time allowed researchers a step-by-step view of the processes involved in an action potential. Their findings caused interest in electrophysiology to skyrocket, eventually inspiring the development of a more precise form of the voltage clamp known as the patch clamp, which allows for the measurement of current across single ion channels. Perhaps most importantly, however, Hodgkin and Huxley's successful efforts at precisely modeling the action potential would lay the groundwork for a more quantitative approach to biology in the twentieth century.Schwiening, C. (2012). A brief historical perspective: Hodgkin and Huxley The Journal of Physiology, 590 (11), 2571-2575 DOI: 10.1113/jphysiol.2012.230458... Read more »

  • July 14, 2014
  • 01:13 PM

Schizophrenic Noise and Schizophrenic Voices

by Gabriel in Lunatic Laboratories

Hear that voice? What is there more than one? Is this real, or fake? How do you know? That is how schizophrenia works: auditory hallucinations, confusion, inability to tell what […]... Read more »

Teal S. Eich,, Derek Evan Nee,, Catherine Insel,, Chara Malapani,, & Edward E. Smith. (2014) Neural Correlates of Impaired Cognitive Control over Working Memory in Schizophrenia. Biological psychiatry, 76(2). info:/10.1016/j.biopsych.2013.09.032

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