OBSCN

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".

From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study, published on August 2 in the journal Cell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. "There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone," says senior author John Perry, a geneticist and professor at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, U.K. "We're not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks." To untangle sex's role in obesity risk, the research team sequenced the exome -- the protein-coding part of the genome -- of 414,032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Based on height and weight, BMI is an estimated measurement of obesity. The search turned up five genes influencing BMI in women and two in men. Among them, faulty variants of three genes -- DIDO1, PTPRG, and SLC12A5 -- are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had obesity, as approximated by their BMI. Individuals carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men. Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants' recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size. "What's quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death," says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. "There's currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity." Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity. "We're at the very earliest stages of identifying interesting biology," says Perry. "We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity."

▎Armstrong2022年8月11日，正大天晴新型双抗技术平台专利公开。该双抗的设计为一侧Fab的CH1和CL分别被HLA-I α3和β2所取代，以避免轻链的错配，正大天晴采用该技术研发了CD38/CD3双抗。这一设计与药明生物WuxiBody的设计类似，WuxiBody的CH1和CL被TCRα和β联取代。正大天晴此前曾引进WuxiBody技术开发了CD3/CD20双抗并采用2:1 TCB的价态设计。采用类似设计思路的还有恒瑞医药的HOT-Ig，以Obscurin（遮蔽蛋白）和Titin（肌联蛋白）取代CH1和CL。恒瑞医药已经申报了PVRIG/TIGIT双抗。总结近年来正大天晴在大分子领域积极布局，双抗管线包括CD3/CD20、PD-1/TGFβ和PD-L1/TGFβ。ADC方面，国内多家药企多对标第一三共的DXd-ADC，开发类似的技术，正大天晴则选择直接开发氘代DXd-ADC。在治疗领域方面，正大天晴集中在肿瘤、肝病、呼吸、感染为其布局重点。----------------------感兴趣的读者可以加入“医药笔记”知识星球。Armstrong技术全梳理系列GPRC5D靶点全梳理；CD40靶点全梳理；CD47靶点全梳理；补体靶向药物技术全梳理；补体药物：眼科治疗的重要方向；Claudin 6靶点全梳理；Claudin 18.2靶点全梳理；靶点冷暖，行业自知；中国大分子新药研发格局；被炮轰的“me too”；佐剂百年史；胰岛素百年传奇；CUSBEA：风雨四十载；中国新药研发的焦虑；中国生物医药企业的研发竞争；中国双抗竞争格局；中国ADC竞争格局；中国双抗技术全梳理；中国ADC技术全梳理；Ambrx技术全梳理；Vir Biotech技术全梳理；Immune-Onc技术全梳理；科济药业技术全梳理；恺佧生物技术全梳理；同宜医药技术全梳理；百奥赛图技术全梳理；腾盛博药技术全梳理；创胜集团技术全梳理；永泰生物技术全梳理；中国抗体技术全梳理；德琪医药技术全梳理；德琪医药技术全梳理2.0；和铂医药技术全梳理；荣昌生物技术全梳理；再鼎医药技术全梳理；药明生物技术全梳理；恒瑞医药技术全梳理；豪森药业技术全梳理；正大天晴技术全梳理；吉凯基因技术全梳理；基石药业技术全梳理；百济神州技术全梳理；百济神州技术全梳理第2版；信达生物技术全梳理；信达生物技术全梳理第2版；中山康方技术全梳理；复宏汉霖技术全梳理；先声药业技术全梳理；君实生物技术全梳理；嘉和生物技术全梳理；志道生物技术全梳理；道尔生物技术全梳理；尚健生物技术全梳理；康宁杰瑞技术全梳理；科望医药技术全梳理；科望医药技术全梳理2.0；岸迈生物技术全梳理；礼进生物技术全梳理；康桥资本技术全梳理；余国良的抗体药布局；荃信生物技术全梳理；安源医药技术全梳理；三生国健技术全梳理；仁会生物技术全梳理；乐普生物技术全梳理；同润生物技术全梳理；宜明昂科技术全梳理；派格生物技术全梳理；迈威生物技术全梳理；Momenta技术全梳理；NGM技术全梳理；普米斯生物技术全梳理；普米斯生物技术全梳理2.0；三叶草生物技术全梳理；贝达药业抗体药全梳理；泽璟制药抗体药全梳理；恒瑞医药抗体药全梳理；齐鲁制药抗体药全梳理；石药集团抗体药全梳理；豪森药业抗体药全梳理；华海药业抗体药全梳理；科伦药业抗体药全梳理；百奥泰技术全梳理；凡恩世技术全梳理。