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Slow Release of a Drug, TT-10, Improves Heart Attack Recovery in a Mouse Model

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BIRMINGHAM, Ala. – A heart attack kills heart muscle cells, leading to a scar that weakens the heart, often leading to eventual heart failure. The lack of muscle repair is due to the very limited ability of mammalian heart muscle cells to proliferate, except for a brief period around birth.

BIRMINGHAM, Ala. – A heart attack kills heart muscle cells, leading to a scar that weakens the heart, often leading to eventual heart failure. The lack of muscle repair is due to the very limited ability of mammalian heart muscle cells to proliferate, except for a brief period around birth.

Thus, a pharmaceutical product called TT-10, which acts through components of the Hippo-Yap signaling pathway to spur proliferation of heart muscle cells, was thought to offer promise to treat heart attacks. Intraperitoneal injections of TT-10 in a mouse heart-attack model several years ago at first promoted proliferation of heart muscle cells and showed declines in the size of the dead area of heart muscle, known as an infarct, one week after administration. However, those early improvements were followed by worsened cardiac function at later time points.

So, Jianyi “Jay” Zhang, M.D., Ph.D., and his University of Alabama at Birmingham Department of Biomedical Engineering colleagues asked a simple question: What would happen if TT-10 were loaded into nanoparticles made of poly-lactic-co-glycolic-acid, or PLGA, which would then allow the slow release of TT-10?

Slow release indeed turned out to be beneficial, as Zhang and UAB colleagues report in the journal JCI Insight. Nanoparticle-mediated, slow-release delivery of TT-10 enhanced the potency and durability of TT-10 treatment for repair of heart muscle in the mouse heart-attack model.

Injection of the TT-10 nanoparticles into the infarcted heart muscle improved heart function — as measured by significantly improved ejection fractions and functional shortening, and significant decreases in end-systolic diameters and end-diastolic diameters — as compared with groups of mice treated with saline, empty nanoparticles or direct TT-10 solution. Also, the TT-10 nanoparticle-treated hearts had significantly lower infarct sizes and lower heart-weight/body-weight ratios compared to the other three groups, which all had similar measurements. All these measures indicated improved heart function for the TT-10 nanoparticle group.

The researchers also measured the effects of TT-10 on the biology of heart muscle cells, known as cardiomyocytes, and on several markers of cell reproduction, both in culture and in the mouse heart-attack model.

Human induced pluripotent stem-cell cardiomyocytes grown in different concentrations of TT-10 showed increased molecular markers for proliferation, the S-phase of the cell cycle (when the cell replicates its genome content), the M-phase of the cell cycle (when the cell divides the copied DNA) and cytokinesis (when the cytoplasm of the two daughter cells is split in two). Peak activity was seen at TT-10 concentrations of 10 to 20 micromolar.

The cultured cardiomyocytes also showed significantly reduced programmed cell death, or apoptosis, and a significantly increased proportion of cardiomyocytes with the transcriptional co-activator Yap located in the nuclei. That presence of Yap in the nucleus, where it actively aids gene expression, is consistent with a role for Hippo-Yap signaling in cardiac regeneration, Zhang says.

Hearts treated with TT-10 nanoparticles in the mouse heart-attack model had dramatically more border-zone cardiomyocytes that showed markers for cell proliferation, M-phase growth and nuclear location of Yap at one week after infarction, compared to the other three treatment groups. The border zone is the area next to the infarct. Also, the TT-10 nanoparticle treatment appeared to promote blood vessel growth, called angiogenesis.

This suggests that the improvements in myocardial recovery observed in TT-10 nanoparticle-treated mice appeared to be, at least partially, attributable to the activation of Hippo-Yap signaling and cardiomyocyte proliferation, the UAB researchers say.

“Thus, our results suggest that PLGA nanoparticles could be used to improve the efficiency of treatment administration for numerous cardiovascular drugs,” Zhang said. “Furthermore, although the animals in our current investigation were treated with TT-10 nanoparticles via direct intramyocardial injections during open-chest surgery, PLGA nanoparticles are fully compatible with less invasive clinical delivery methods, such as catheter-based or echo-guided transthoracic myocardial injection.”

Co-authors with Zhang in the study, “TT-10-loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction,” are Wangping Chen, Danielle Pretorius, Yang Zhou and Yuji Nakada, UAB Department of Biomedical Engineering; and Jinfu Yang, Second Xiangya Hospital, Central South University, Changsha, China. Chen is a visiting scholar from Second Xiangya Hospital, Central South University.

Support came from National Institutes of Health grants HL114120, HL131017, HL149137 and HL134764.

Biomedical Engineering is a joint department of the UAB School of Medicine and the UAB School of Engineering. Zhang is professor and chair of the department, and he holds the T. Michael and Gillian Goodrich Endowed Chair of Engineering Leadership.

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Original Source: bioengineer.org

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Earliest Evidence of Humans Decorating Jewellery in Eurasia

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Upon their dispersals in Central and Western Europe by around 42,000 years ago, groups of Homo sapiens started to manipulate mammoth tusks for the production of pendants and mobiliary objects, like carved statuettes, at times decorated with geometric motifs. In addition to lines, crosses and hashtags, a new type of decoration – the alignment of punctuations – appeared in some ornaments in south-western France and figurines in Swabian Jura in Germany. Until now, most of these adornments were discovered from older excavations, and their chronological attributions remain uncertain. Hence, questions regarding the emergence of human body augmentation and the diffusion of mobiliary art in Europe remained strongly debated.

Upon their dispersals in Central and Western Europe by around 42,000 years ago, groups of Homo sapiens started to manipulate mammoth tusks for the production of pendants and mobiliary objects, like carved statuettes, at times decorated with geometric motifs. In addition to lines, crosses and hashtags, a new type of decoration – the alignment of punctuations – appeared in some ornaments in south-western France and figurines in Swabian Jura in Germany. Until now, most of these adornments were discovered from older excavations, and their chronological attributions remain uncertain. Hence, questions regarding the emergence of human body augmentation and the diffusion of mobiliary art in Europe remained strongly debated.

A new study, led by researchers of the Max Planck Institute for Evolutionary Anthropology in Germany, the University of Bologna in Italy, Wroclaw University in Poland, the Polish Geological Institute-National Research Institute, Warsaw, Poland, and the Institute of Systematics and Evolution of Animals Polish Academy of Sciences, reports the oldest known punctate ivory pendant found in Eurasia. Its age of 41,500 years places this personal ornament from Stajnia Cave within the record of the earliest dispersals of Homo sapiens in Europe.

Methodological advances in radiocarbon dating

“Determining the exact age of this jewellery was fundamental for its cultural attribution, and we are thrilled of the result. This work demonstrates that using the most recent methodological advances in the radiocarbon method enables us to minimise the amount of sampling and achieve highly precise dates with a very small error range. If we want to seriously solve the debate on when mobiliary art emerged in Palaeolithic groups, we need to radiocarbon date these ornaments, especially those found during past fieldwork or in complex stratigraphic sequences”, says Sahra Talamo, lead author of the study and director of the BRAVHO radiocarbon lab at the Department of Chemistry G. Ciamician of Bologna University.

The study of the pendant and the awl was also carried out through digital methodologies starting from the micro-tomographic scans of the finds. “Through 3D modeling techniques, the finds were virtually reconstructed and the pendant appropriately restored, allowing detailed measurements and supporting the description of the decorations,” notes co-author Stefano Benazzi, director of the Osteoarchaeology and Paleoanthropology Laboratory (BONES Lab) at the Department of Cultural Heritage, University of Bologna.

The personal ornament was discovered in 2010 during fieldwork directed by co-author Mikolaj Urbanowski among animal bones and a few Upper Palaeolithic stone tools. Separate short term occupations by Neanderthals and Homo sapiens groups have been identified from the cave’s archaeological record. The disposal of the pendant is probably occurred duringa hunting expedition into the Krakow-Czestochowa Upland where the pendant broke and was left behind in the cave.

Similar decorations appeared independently across Europe

“This piece of jewellery shows the great creativity and extraordinary manual skills of members of the group of Homo sapiens that occupied the site. The thickness of the plate is about 3.7 millimetres showing an astonishing precision on carving the punctures and the two holes for wearing it”, says co-author Wioletta Nowaczewska of Wroclaw University. “If the Stajnia pendant’s looping curve indicates a lunar analemma or kill scores will remain an open question. However, it is fascinating that similar decorations appeared independently across Europe”, remarks co-author Adam Nadachowski from the Institute of Systematics and Evolution of Animals Polish Academy of Sciences.

In broad-scale scenarios on the earliest expansion of Homo sapiens in Europe, the territory of Poland is often excluded suggesting that it remained deserted for several millennia after the demise of Neanderthals. “The ages of the ivory pendant and the bone awl found at Stajnia Cave finally demonstrate that the dispersal of Homo sapiens in Poland took place as early as in Central and Western Europe. This remarkable result will change the perspective on how adaptable these early groups were and call into question the monocentric model of diffusion of the artistic innovation in the Aurignacian”, says co-athor Andrea Picin from the Max Planck Institute for Evolutionary Anthropology in Leipzig.

Further detailed analyses on the ivory assemblages of Stajnia Cave and other sites in Poland are currently underway and promise to yield more insights into the strategies of production of personal ornaments in Central-Eastern Europe.

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Article: bioengineer.org

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Follow the Boat, Find the Bird — Free Food From Trawlers Helps Identify Important Areas for Seabird Conservation

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. Seabird populations under threat due to human activity
. University College Cork research could have implications for offshore developments
. Birds with tracking devices found to follow fishing vessels for food

. Seabird populations under threat due to human activity
. University College Cork research could have implications for offshore developments
. Birds with tracking devices found to follow fishing vessels for food

Studying fishing boats’ routes could assist better coastal planning and ultimately protect threatened seabirds, according to new research from University College Cork (UCC).

An international team, led by the Marine Ecology Group at MaREI, the SFI Research Centre for Energy, Climate and Marine hosted by UCC, equipped seabirds with the latest tracking technology and found that fishing vessels can help figure out where the birds go to feed.

Northern fulmars, a relative of the albatross, were shown to travel hundreds of kilometres in a matter of days for a meal before returning home, and their tracks revealed that up to half of the fulmars were following fishing vessels for food in the form of fishing waste thrown overboard.

The researchers then looked at the wider distribution of fulmars around Irish and UK waters and found that areas of the sea that fishing vessels spent the most time in were also where fulmars went to feed. Northern fulmars are an endangered species in Europe with markedly declining populations. This new understanding of their feeding grounds is vitally important for protecting them from the hazards they may face at sea at a time when most of the world’s seabird populations are threatened. Fulmars are often accidentally caught by vessels. Because fulmars can live to 50 years old, even occasional bycatch in fishing gear can have big implications for their population. This study highlights the need for best practice when fishing, including bird scaring lines when setting nets or trailing longlines.

Lead author Jamie Darby of MaREI at UCC said:

“Information about where seabirds go at sea is vital for making sure that new offshore developments, including windfarms, can be designed to do the least amount of harm. That’s why studies such as this one are so important.

“Humans have given seabirds a lot to contend with. They are sensitive to oil and plastic pollution; we accidentally catch them in commercial fishing gears; we’ve brought rats and other invasive species onto many of their breeding colonies over the last few centuries.”

Ireland has a huge expanse of marine territory and attracts fishing vessels from overseas because these fishing grounds are so productive. Ireland’s commitment to renewable energy means that windfarms will soon be a common fixture along the coasts. However given the islands and cliffs of Ireland are home to 24 species of seabird, proper planning of these energy generators is essential if these birds are to be protected.

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Original Article: bioengineer.org

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Unveiling the Hidden Cellular Logistics of Memory Storage in Neurons

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Exploring the mechanisms involved in sleep-dependent memory storage, a team of University of Michigan (U-M) cellular biologists found that RNAs associated with an understudied cell compartment in hippocampal neurons vary greatly between sleeping and sleep-deprived mice after learning.

Exploring the mechanisms involved in sleep-dependent memory storage, a team of University of Michigan (U-M) cellular biologists found that RNAs associated with an understudied cell compartment in hippocampal neurons vary greatly between sleeping and sleep-deprived mice after learning.

Sara Aton, Associate Professor in the Department of Molecular, Cellular, and Developmental Biology, and James Delorme, a recent U-M neuroscience graduate student, hypothesized that both a learning event and subsequent sleep (or sleep loss) would impact mRNA translation. Most prior work on the effects of sleep on mRNAs have focused on transcripts in the neuronal cytosol. However, Drs. Aton and Delorme found that after learning, major changes in RNAs are instead present –almost exclusively– on ribosomes associated with neuronal cell membranes. These results have been published in the Proceedings of the National Academy of Sciences, in November 30, 2021.*

The team first applied a commonly used biochemical method that homogenizes and centrifuges the hippocampal tissue, to separate the cytosol (the aqueous component of the cytoplasm of acell within which smaller organelles and particles are suspended) from other cellular components that are usually considered “debris” (endoplasmic reticulum, golgi apparatus, cell membrane, etc.). In this study, the authors found that RNA associated with ribosomes in the cytosol varied depending on whether the animals slept or not, confirming prior transcriptomic studies. However, cytosolic ribosomes showed almost no RNA changes depending on prior learning.

“If we had just stopped there, we wouldn’t have found anything that was novel or insightful. We strongly felt that we had to rethink our methodology,” explained Aton. Since it is well known that the endoplasmic reticulum is covered with ribosomes, the machinery that converts RNAs into proteins, Delorme and Aton decided to sequence the RNAs in the other parts of the cell, the “debris,” outside of the cytosol. It is in the less-well-studied membrane-containing cell fraction that they found that many transcripts were affected as a function of prior learning. These modified transcripts also differed significantly whether the animals had been allowed to sleep following the learning – allowing a new memory to be stored – or if they had been sleep-deprived. These unexpected results open the door to many more investigations.

“By looking in those other areas of the cell, we now have the capacity to generate many new hypotheses about what happens at the molecular level when memories are consolidated, and when consolidation is interrupted due to sleep deprivation,” said Aton.

For example, in the animals that slept following learning, Aton and Delorme observed an increase in the abundance of transcripts that encode components of protein synthesis machinery in the membrane fraction of hippocampal neurons. One hypothesis would be to test whether there is indeed an increase in protein production by membrane-associated ribosomes after post-learning sleep.

In addition to mRNAs, the authors also found that learning led to changes in long non-coding RNAs’ association with neuronal membrane-bound ribosomes. These could play a role in regulating the translation of other transcripts, which should be investigated. “The cells have developed very elegant mechanisms to fine tune the process from transcription to translation, and long non-coding RNAs could be one of them in this part of the brain,” said Aton.

She further explained by comparing neurons to a large warehouse, with complex logistics that are needed to respond quickly to needs for new proteins in distant cell processes, requiring preparedness and distribution adaptation processes. “Neurons have to deliver the ‘package’ within a reasonable time frame, when it’s needed, no matter how far away that location is. Neurons have evolved to do this, and it is a huge biological question to investigate. It is important to understand how this biology works because – in addition to storing new memories – it impacts regeneration, degeneration, and neurological diseases,” concluded Aton.

This is the second PNAS publication from the Delorme-Aton team’s research. In their first article** (see press release), the team found, in sleep-deprived mice, an inhibitory gating mechanism that could disrupt hippocampal activity and memory consolidation. In contrast, post-learning sleep suppressed the activity of inhibitory interneurons, increased activity among surrounding hippocampal neurons, and improved memory storage.

Papers cited:

* “Hippocampal neurons’ cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep,” James Delorme, Lijing Wang, Varna Kodoth, Yifan Wang, Jingqun Ma, Sha Jiang, Sara J. Aton, Proceedings of the National Academy of Sciences, November 30, 2021, https://doi.org/10.1073/pnas.2108534118

** “Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity, to inhibit memory consolidation,” James Delorme, Lijing Wang, Femke Roig Kuhn, Varna Kodoth, Jingqun Ma , Jessy D. Martinez, Frank Raven, Brandon A. Toth, Vinodh Balendran, Alexis Vega Medina, Sha Jiang, Sara J. Aton, PNAS, June 21, 2021, 10.1073/pnas.201931811

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