titin

Uncertainty surrounding how truncated titin proteins (TTNtvs) cause dilated cardiomyopathy (DCM) and peripartum cardiomyopathy (PPCM) led to investigations that could better inform therapies for these conditions. Advancements in the study of two rare heart conditions -- peripartum cardiomyopathy (PPCM), and dilated cardiomyopathy (DCM) -- contributed by researchers at the Perelman School of Medicine at the University of Pennsylvania may serve as critical guides in future work toward developing therapies for the conditions. The lab of Zoltan Arany, MD, PhD, the Samuel Bellet Professor of Cardiology and a professor of Cell and Developmental Biology, published their findings this month in the New England Journal of Medicine (NEJM), adding to separate research they recently published in the Journal of Clinical Investigation (JCI). PPCM is a severe cardiac condition affecting approximately 1 in 1,000 pregnant or recently pregnant women, characterized by the weakening of the heart muscle, leading to reduced cardiac function. Certain factors increase the risk of developing PPCM, including advanced maternal age, multiple gestations (twins or more), anemia, and hypertensive disorders of pregnancy. Black women in the United States are at a much higher risk compared to White women, for reasons that remain unclear. Treatment for PPCM generally involves standard heart failure management strategies, including medications like diuretics, beta-blockers, and ACE inhibitors. In severe cases, advanced therapies such as LVADs or heart transplantation may be considered. Unlike PPCM, DCM can occur at any age and is not specifically related to pregnancy and affects about 1 in 100 people. Risk factors for DCM can include a family history of heart disease, certain infections, exposure to toxins, and other underlying heart conditions. The recent JCI study focused on the role of genetic variants in the TTN gene, which encodes for a crucial protein called titin. Titin acts like a spring, playing a vital role in the assembly and regulation of heart muscle contraction. The study sheds light on how specific genetic variants, known as truncating variants (TTNtvs), in the TTN gene may contribute to DCM. Arany and his team developed a patient-specific antibody to detect these TTNtvs in human heart tissue. Using this novel approach, they found that TTNtvs are present in hearts affected by DCM, indicating a potential link between these genetic variants and the development of the disease. The study also revealed that the truncated titin proteins associated with TTNtvs integrate into the heart's muscle structure. This suggests that these genetic variants may impact the sarcomere, the basic unit of heart muscle, influencing its structure and function. Meanwhile, the recent article in the NEJM consolidates the current state of knowledge about PPCM, while providing a roadmap for navigating the complexities of the disease. Past research from the Arany lab has highlighted the racial disparities in PPCM, with Black women in the US being four times more likely than White women to develop the disease. The NEJM article emphasizes the critical need for early diagnosis and the development of effective management strategies, given that PPCM is now a leading cause of maternal mortality in many parts of the world. "There is a great need for further research into long-term outcomes, racial disparities, and the underlying mechanisms of PPCM," said Arany. "We hope our recent research signals a call to action for the medical community to address this critical issue affecting young women, their families, and newborns." There is a profound lack of research in peripartum cardiomyopathy (PPCM), which limits expert's ability to find the best way to treat, and ultimately prevent it. In order to make important discoveries, doctors at the Perelman School of Medicine created PPCM-R, the first patient-focused registry about PPCM. Among the goals of the PPCM-R is to create a database of PPCM survivor medical records driven by patients, and to answer important research questions and ultimately prevent PPCM. The work was supported by grants from the National Heart, Lung, and Blood Institute (HL152446, HL126797, HL149891), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-53461-12), the Children's Hospital of Philadelphia Frontier Program, Foundation Leducq Research Grant no. 20CVD01, and by the Center for Engineering Mechanobiology through a grant from the National Science Foundation's Science and Technology program (15-48571).

A team of researchers describes the mechanism by which the MEC-2 protein condensates of the touch receptor neurons transition from fluid to solid-like states, switching their role in the transmission of mechanical forces. These findings pave the way for developing innovative therapies and treatments.   A team of researchers describes in Nature Cell Biology the mechanism by which the MEC-2 protein condensates of the touch receptor neurons transition from fluid to solid-like states, switching their role in the transmission of mechanical forces. These findings pave the way for developing innovative therapies and treatments. Touch plays a fundamental role in our physical, emotional, and social well-being. From a primary way of conveying emotions to sensory integration, it is crucial for the complex growth of cognitive, emotional, social, and behavioral abilities especially during the early development of infants and children. Touch allows us to build connections with others, eases pain and stress, and helps us to understand the world around us giving crucial information such as the texture, temperature, and shape of objects. When sensing any stimuli, such as when the body is being touched, the mechanical signals are transformed into biological responses that help us to adapt to continuously changing environments. This transformation involves a variety of intracellular and molecular processes inside the cells that enable us to perceive and respond to tactile stimuli effectively converting the physical stimuli into electrical activity. The ability of cells to sense and transmit mechanical forces depends on the correct assembly, localization and mechanical properties of the protein complexes in the force transmission pathway. Often, large macromolecular protein complexes form liquid-like condensates in a process akin to phase separation. Such biomolecular condensates are found in many, if not all, eukaryotic cells, and play a vital role in various physiological and pathological processes, constituting a promising clinical target. Due to the liquid-like nature of these biomolecular condensates, their role in mechanotransduction, that is, any mechanism by which cells convert mechanical stimulus into electrochemical activity, is not clear. Although studies have shown that their material properties can change from liquid to solid over time, there is one remaining question: Can these condensates, with different material properties, have different biological functions? Examining MEC-2 protein condensates in touch receptor neurons To address the question, ICFO researchers Neus Sanfeliu, Frederic Català, Iris Ruider, Montserrat Porta and Stefan Wieser, led by Prof. Michael Krieg, in collaboration with IRB Barcelona researchers Borja Mateos, Carla Garcia, Maria Ribera and Adrià Canals, led by ICREA Prof. Xavier Salvatella, publish a study in Nature Cell Biology identifying the mechanism by which specific protein condensates transition from liquid to solid states, enabling the stability and transmission of the mechanical forces. The focus of the study was the MEC-2 protein member of the Stomatin family, which is essential for the membrane mechanics and modulation of the ion channel activity. Sanfeliu and the team found that MEC-2 also forms condensates in the touch receptor neurons of the roundworm Caenorhabditis elegans, a model organism widely used for studying the structure and function of the nervous system. The researchers created transgenic animals carrying a single copy of the MEC-2 protein marked with a fluorescent label. Combining fluorescence imaging in an inverted confocal microscope and the FRAP technique, a fluorescence microscopy method, they identified two different MEC-2 populations within the touch receptor neurons: a liquid and mobile pool, close to the cell body, that facilitates transport along the thin neurons; and a solid-like mature population in the distal neurites. They applied mechanical stimuli to the animal's body wall using a hybrid microfluidic-pneumatic device and observed, in combination with the FRET fluorescence microscopy technique used to study molecular interactions, that only mature populations sustain mechanical forces during touch. To analyze in detail the properties of these protein condensates, the researchers reproduced the condensation process in the test tube and performed nuclear magnetic resonance experiments, revealing the molecular mechanisms that lead to condensation and regulate the mechanical properties of the condensates. In addition, by using a technique called optical tweezer microrheology, they studied how the mechanical properties of the purified protein condensates changed over time. Changing from fluid to solid switches the function of condensates With the help of a neuron-specific screen, Sanfeliu and colleagues identified that another protein, UNC-89 from the Titin superfamily, was responsible for promoting MEC-2 condensates rigidity maturation in vivo. This structural transformation led to a shift in their biological function, which switched from facilitating the transport of the protein to facilitating the integration and conversion of mechanical cues during mechanosensation. These findings describe a new biological function of the liquid-to-solid phase transition of the MEC-2 proteins. Even more, they also draw a new role, previously unidentified, for the UNC-89 proteins in the neurons. Given the significant roles that biological condensates play in various physiological and pathological processes, a better understanding of their functions might open new possibilities for innovative therapies and treatments, such as those aimed at understanding the molecular details that drive rigidity transitions in health and disease. "We are really excited about the role of condensate maturation in mechanotransduction," comments Prof. at ICFO Michael Krieg, "and to look for ways to investigate how defects in protein condensation play in the development of neurological disorders ." ICREA Prof. at IRB Barcelona Xavier Salvatella concludes "It has been known for some time that changes in the material properties of condensates can be detrimental and lead to diseases but this work shows how they can also be functional and be regulated by protein-protein interactions. It has been great to contribute to this discovery and we look forward to continuing to work on this together with our colleagues at ICFO " This study is an indication of the successful collaborative efforts both research groups have had in obtaining these results. As Krieg concludes, "We look forward to continue collaborating with Salvatella's research group at IRB Barcelona in the hopes of finding new amazing results that can further help us understand cell mechanical properties on the molecular and systems level, to tackle health and disease issues".

Transition metal dichalcogenide (TMD) semiconductors are special materials that have long fascinated researchers with their unique properties. For one, they are flat, one-atom-thick two-dimensional (2D) materials similar to that of graphene. They are compounds that contain different combinations of the transition metal group (e.g., molybdenum, tungsten) and chalcogen elements (e.g., sulfur, selenium, tellurium). Transition metal dichalcogenide (TMD) semiconductors are special materials that have long fascinated researchers with their unique properties. For one, they are flat, one-atom-thick two-dimensional (2D) materials similar to that of graphene. They are compounds that contain different combinations of the transition metal group (e.g., molybdenum, tungsten) and chalcogen elements (e.g., sulfur, selenium, tellurium). What's even more fascinating is that assembling different TMD layers into vertical stacks creates a new artificial material called a van der Waals (vdW) heterostructure. By incorporating different materials, it becomes possible to combine the properties of individual layers, producing new optoelectronic devices with tailor-made properties. This opens the door to exploring fundamental physics, such as interlayer excitons, twistronics, and many more. However, until now, no scientists have studied whether changing the stacking order affects the spectroscopic properties of these heterostructures. For a long time, the lack of understanding of TMD heterostructures led to a questionable hypothesis that altering the stacking order of the layers does not affect their properties. This was recently debunked by a team of researchers at the Center for Integrated Nanostructure Physics (CINAP), Institute for Basic Science (IBS) in South Korea. Led by Professor LEE Young Hee the group discovered that the sequential order of the layers in heterostructures affects the generation of "dark excitons" within the material. This finding suggested the added importance of considering stacking sequential order dependence of these materials for further use in real device applications. Excitons represent an electron and a positively charged hole (a location where an electron is absent) bound together by electrostatic attraction in a solid material, typically a semiconductor crystal. Monolayer TMD semiconductors have a direct bandgap and exhibit optically accessible "bright excitons." At the same time, there are also "dark excitons," that are challenging to study due to their invisibility. However, the underlying mechanisms that give rise to these anomalies are not fully understood. The IBS researchers observed a remarkable phenomenon: the emergence or disappearance of additional photoluminescence (PL) peaks based on different stacking sequences. This previously unreported effect has been confirmed to be reproducible across multiple heterostructures. The researchers attributed the origin of these additional peaks to the emergence of dark exciton exclusively located in the top layer of the heterostructure, which is further confirmed by scanning tunneling microscopy (STM). Researchers expect that this property can be utilized for optical power switches in solar panels. Dr. Riya SEBAIT, the first author of the study said "Our experimental results clearly demonstrate stacking sequence-dependent anomalous properties, which could potentially pioneer a new field of study named 'fliptronics.' As we flip or invert the heterostructure, bands undergo a unique renormalization." A clean, residue-free interface is necessary to investigate stacking sequential dependent properties. This study represents a significant breakthrough as this was the first time. It was demonstrated that altering the stacking sequential order in the heterostructure can lead to changes in its physical properties. Researchers attempted to explain this flip-induced phenomenon by looking into the microscopic many-particle model, which suggests that layer-dependent strain could be one possible solution to this puzzle. Assuming that the top layer becomes more strained compared to the bottom layer, the calculated data using the theoretical model shows good agreement with the experimental results. This suggests that this stacking sequence-dependent requires further study, not only for understanding the underlying physics but also for its real-device applications. Furthermore, this study also facilitates the utilization of momentum-forbidden dark excitons, as due to the unique band renormalization at the heterostructure, it is possible to convert them into bright excitons. Prof. Young Hee Lee, the main-corresponding author remarks that "This exceptional phenomenon of the emergence of dark excitons at the bilayer heterostructure will inspire other researchers to delve deeper into understanding and harnessing these extraordinary properties towards applications." This work was done in interdisciplinary collaborations with Prof. Ermin MALIC at Philipps-Universität Marburg, Germany, and research fellow SEOK Jun Yun from Oak Ridge Laboratory, USA.