This important discovery is laid out in their paper published today in Nature Structural & Molecular Biology. The paper is titled “The structure of the stress induced photosystem I — IsiA antenna supercomplex.”

“Supercomplexes are associations between antennae proteins and photochemical reaction centers that exist in all photosynthetic organisms,” explained Yuval Mazor, an assistant professor in the School of Molecular Sciences and the Biodesign Institute’s Center for Applied Structural Discovery. “This particular one comes from cyanobacteria, the class (phyla) of bacteria in which oxygenic photosynthesis first appeared (a few billion years ago) and later evolved, into all types of oxygenic photosynthesis that we know today.”

Mazor’s team includes Hila Toporik, a postdoctoral fellow, and Jin Li, a graduate student; and a collaboration with Assistant Professor Po-Lin Chiu, who all belong to the School of Molecular Sciences and the Center for Applied Structural Discovery, as well as Dewight Williams, an associate research scientist in the John M. Cowley Center for High Resolution Electron Microscopy.

Plants, algae and cyanobacteria use photosynthesis to produce oxygen and reduced carbon, like carbohydrates, which builds and fuels our entire biosphere. There are two pigment-protein complexes that orchestrate the primary light reactions in oxygenic photosynthesis: photosystem I (PSI) and photosystem II (PSII). Understanding how these photosystems work their magic is one of the long-sought goals of science.

Physicist and Nobel laureate Richard Feynman once famously stated, “It is very easy to answer many fundamental biological questions; you just look at the thing!” Indeed, the central idea behind structural biology is that once one is able to “look” at “things” in great enough detail to discern their atomic structures, one will naturally be able to answer how and why the components and players of complex biological processes work the way they do.

In the past few years, single-particle cryogenic electron microscopy (cryo-EM) in particular has triggered a revolution in structural biology and has become a newly dominant discipline. Cryo-EM allows researchers to take a look at biological structures that were simply not accessible just a few years ago, and is now exposing structures of unprecedented complexity in great detail.

Indeed it is this technique utilized by the experts in the School of Molecular Sciecnes and The College of Liberal Arts and Sciences at ASU that has enabled the elucidation of the structure of the PSI-IsiA complex. In the lab, this particular super-complex is produced by cyanobacteria under low iron environment or excessive light fluxes. However, in the “real world” iron exists at very low concentrations and high light can be the rule rather than the exception, so ultimately PSI-IsiA is a very common form of photosystem I, one of the two essential engines of photosynthesis.

The complex is unique in size, the largest photosynthetic supercomplex with a known molecular structure, and in complexity with more than 700 different molecules (mostly light-harvesting molecules) making up the complete structure.

There are 591 chlorophylls in the PSI-IsiA supercomplex, by far the largest number of bound pigments in any of the photosynthetic super-complexes with known structures.

The ability of cyanobacteria to express this complex when they are under stress plays an important role in their survival under these conditions. This complex also represents a large class of antennae that are very common in marine cyanobacteria, which are responsible for a considerable fraction of the total global photosynthesis output (estimates vary between 15% and 25%). Mazor emphasizes that their work was done on a common laboratory strain, not on one of the marine species.

The current structure uncovers the most crucial details of this enormous machine. As the first example from the cyanobacterial branch of the membrane embedded antenna proteins, it lays a path for evaluating the light-harvesting and photoprotection mechanism (from excess or fluctuating light conditions) in cyanobacteria.

Understanding the complexity and functions of the IsiA photosynthetic supercomplex will ultimately help to ensure that we have a stable energy supply on Earth, undoubtedly one of the central challenges of the 21st century.

The authors would like to acknowledge the use of the Titan Krios at the Erying Materials Center at Arizona State University and the funding of this instrument by NSF MRI 1531991. This study is funded by a startup grant from Arizona State University.

Dr. Patricia Conrod, at Université de Montréal, studied the year-to-year changes in alcohol and cannabis use and cognitive function in a sample of adolescents consisting of 5% of all students entering high school in 2012 and 2013 in the Greater Montreal region (a total of 3,826 7th grade students). Students were assessed annually for 4 years on alcohol and cannabis use, and their cognitive function was evaluated using computarized cognitive tests. The researchers found substance use to be linked to low cognitive functioning, a finding that could be indicative of an underlying common vulnerability. Cannabis use was linked to impairments in working memory and inhibitory control, which is required for self-control. Cannabis use was also linked to deficits in memory recall and perceptual reasoning. Alcohol use was not linked to impairments in these cognitive functions, suggesting cannabis could have more long-term effects than alcohol.

More recently Dr. Conrod’s team analysed the sex difference in cannabis response in the same sample of adolescents. Preliminary data indicates that cannabis use had a stronger effect on the memory functions of male students than female students. Both sexes were however, equally affected by cannabis on inhibitory control. These results help identify at-risk youth groups and target them for early intervention and information.

Dr. Steven Laviolette presented research on the effect the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol or THC, on the adolescent brain, in rodent animal models. His team demonstrated that adolescent exposure to THC induces changes in specific a region of the brain called the prefrontal cortex (PFC) and in a brain circuit, the mesolimbic pathway, that closely resemble the abnormalities observed in schizophrenia. Furthermore, adolescent THC exposure also caused affective and cognitive abnormalities including deficits in social interactions, memory processing and anxiety regulation.

Interestingly, Dr. Laviolette’s team found that administration of drugs that restore normal PFC function in early adulthood could reverse the effects of adolescent THC exposure. They also demonstrated that co-administering THC with drugs that prevent the THC-induced disruption in brain signaling pathways prevented the development of schizophrenia-like effects. These results offer insights into ways to prevent or reverse THC-induced brain signaling defects in adolescents.

Dr. Iris Balodis, from McMaster University, investigates the mechanisms that motivate individuals to act and make decisions that can go against a person’s best interest, as seen in people suffering from addiction. To compare decision-making in individuals suffering from cannabis addiction (also called cannabis use disorder) to healthy controls, Dr. Balodis used an effort-based decision-making test, which explores how much effort and individual is willing to make to receive a given reward. Participants are given a choice between an easy task or a hard task in which they can gain varying amounts of money (for example, pressing a lever a number within a certain time limit). During the administration of this test, Dr. Balodis and her team looked at differences in activity in different brain regions by functional magnetic resonance imaging. Initial findings suggest that there are differences in encoding the value of the reward (money received) and of the effort cost (amount of work done) in individuals addicted to cannabis relative to healthy controls. These were revealed by differences in activation of specific brain regions known to be important for motivation. This information could be key to finding cannabis addiction vulnerability factors.

Adolescent cannabis use is associated with behavioral changes related to reward and motivation in humans. Paradoxically, this use has both been suggested to increase motivation for other drug use (the gateway hypothesis) and a potential “amotivation syndrome” in which individuals are less willing to expend effort to receive a reward. It is not known whether adolescent cannabis use causes either of these responses, or if cannabis use is rather a symptom of a pre-existing state that results in these behaviours. In order to better understand the long-term effects of adolescent cannabis exposure on the brain, Dr. Jibran Khokhar, from the University of Guelph, studied the effect of THC exposure in adolescent rats on their adult behaviour. In this study, adolescent THC exposure differentially impacted instrumental (decreased lever pressing) and Pavlovian learning (increased sign-tracking). These rats also showed differences in other reward-related behaviors. These behavioural changes were accompanied by changes in the connection between different regions of the brain, including those involved in encoding reward and motivation. These results suggest adolescent cannabis exposure in rats can produce long-lasting changes in brain circuitry which might contribute to the behavioral changes observed after cannabis exposure.

Taken together, the research results presented in this symposium help decipher the links between cannabis use and long-lasting changes in the brain, which underlie changes in behaviour in adolescent humans, and in studies reverse-translating these findings to animal models. Research in humans shows that adolescent cannabis use is widespread, and associated with defects in working memory, self-control and motivation. Similar results were obtained in animal studies, through which researchers were also able to test therapies that can reverse the effects of adolescent cannabis use in adulthood. These findings provide keys to prevent and treat the long term effect of adolescent cannabis use.

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“Adhering to a complex medication regimen is a huge challenge for elderly patients with heart failure,” said co-principal investigator Professor Martin Schulz, of the Department of Clinical Pharmacy, Freie Universitaet Berlin, Germany. “It is estimated that 30% to 50% of patients in Europe are nonadherent to heart failure medications, which results in increased frequency and severity of symptoms such as breathlessness, worsening heart failure and consequent hospitalisations, and higher mortality.”

Nonadherence includes not collecting a prescription, taking a lower dose or less pills than prescribed, drug holidays (during weekends or holidays, or when feeling better), or completely stopping one or more drugs.

The PHARM-CHF trial investigated whether regularly seeing a pharmacist improves adherence to heart failure medications. A total of 237 ambulatory chronic heart failure patients aged 60 years and older were randomly allocated to usual care or a pharmacy intervention and followed-up for a median of two years. The average age was 74 years, 62% were male, and the median number of different drugs was nine.

The intervention started with a medication review. Patients brought their drugs to a pharmacist who made a medication plan, checked for drug interactions and double medications, and contacted the physician about any risks. Patients then visited the pharmacy every 8-10 days to discuss adherence and symptoms, and have blood pressure and pulse rate measurements. Drugs were provided in a pillbox with compartments for morning, noon, evening, and night on each day. The pharmacist updated the medication plan if needed and contacted the doctor with new drug-related problems or significant changes in vital signs.

The primary efficacy endpoint was the proportion of days three heart failure medications were collected (using pharmacy claims data) in the year after randomisation. The drugs were beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Compared to usual care, the intervention resulted in a significant 5.7% absolute increase in collection.

The researchers also calculated the proportion of patients who collected the three drugs at least 80% of the days under study (defined as adherent) compared to baseline. The proportion of adherent patients increased from 44% to 86% in the pharmacy group and from 42% to 68% in the usual care group — a significant 18%-points difference between groups. Patients in the pharmacy group were three times more likely to become adherent compared to the usual care group. Six patients would need to receive the intervention to achieve at least 80% adherence in one patient.

There was no difference between groups in the primary composite safety endpoint of days lost in the year following randomisation due to unplanned cardiovascular hospitalisations or all-cause death.

Improvement in quality of life was more pronounced in the pharmacy group after one year and significantly better compared to the usual care group after two years. This meant patients in the pharmacy group were less limited in their daily activities and less worried about their disease.

Professor Schulz, who is also director of the Department of Medicine at ABDA — Federal Union of German Associations of Pharmacists, said patients would need to see the pharmacist every week lifelong for the benefits to continue: “The key point is that pharmacy visits need to be used as an opportunity to provide structured care.”

Co-principal investigator Professor Ulrich Laufs, director of the Department of Cardiology, Leipzig University, Germany, said: “Cardiologists and general practitioners would welcome this type of intervention since it does not change the medication that is prescribed but helps patients to follow the treatment strategy.”

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“Our gut microbiota is composed of trillions of microorganisms that have the potential to affect our health,” said study author Dr Cristiane Mayerhofer, of Oslo University Hospital, Norway. “Previous research has reported reduced biodiversity of microbes in the gut of patients with heart failure patients. Today we show for the first time that this is related to low fibre intake.”

The study also linked meat intake to higher levels of trimethylamine-N-oxide (TMAO) in patients with heart failure. Prior research has shown that increased TMAO levels are associated with a greater risk of cardiovascular events, and that gut microbes play a role in its formation.

“We show an important pathway that connects diet, microbial activity, and cardiovascular disease,” said Dr Mayerhofer. “It would be prudent for patients with heart failure to limit their meat intake to two to three times a week.”

To conduct the study, the investigators recruited 84 well-treated patients with chronic heart failure and 266 healthy people. The composition of gut microbes was assessed by sequencing the bacterial 16S rRNA gene in stool samples and compared between the two groups.

Heart failure patients had lower biodiversity of intestinal microbes than healthy controls, with differences in the two main phyla of bacteria present in the human gut. Patients with heart failure had a lower ratio of Firmicutes/Bacteroidetes (F/B) compared to controls, and this difference was even more pronounced when the cause of heart failure was non-ischaemic

Dietary and outcome analyses were performed in heart failure patients. Patients who had a heart transplant or died had lower biodiversity and a lower F/B ratio than controls. Regarding diet, bacterial diversity and Firmicutes levels were positively associated with fibre intake.

“Our findings suggest that the altered microbiota composition found in patients with chronic heart failure might be connected to low fibre intake,” said Dr Mayerhofer. “If these findings are confirmed in future studies, my advice will be to choose foods high in fibre such as cereals, fruits and vegetables to stimulate a healthy gut flora.”

“We are still just in the beginning of mapping and understanding the microbiota, how it works, and its potential for the clinical setting,” noted Dr Mayerhofer.

She is currently involved with GutHeart, the first randomised controlled trial on the effect of a probiotic and an antibiotic on the composition of gut bacteria, heart function, and inflammation in patients with heart failure.2 “The trial will show the potential clinical effects of modulating our gut bugs in the setting of heart failure,” she said.

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