University of Porto

小胶质细胞以其在中枢神经系统中的免疫和保护作用而闻名。这些功能需要小胶质感觉体的协调响应，其中细胞表面的模式识别受体(PRRs)识别病原体相关分子模式(PAMPs)和组织损伤相关分子模式(DAMPs) 小胶质细胞以其在中枢神经系统中的免疫和保护作用而闻名。这些功能需要小胶质感觉体的协调响应，其中细胞表面的模式识别受体(PRRs)识别病原体相关分子模式(PAMPs)和组织损伤相关分子模式(DAMPs)是最关键的参与者。PAMPs，如nod样受体(NLRs)和toll样受体(TLRs)，通常识别存在于各种病原体中的结构保守分子。受损细胞释放的DAMPs(如ATP、谷氨酸、DNA、RNA)通常与将小胶质细胞吸引到受损部位有关。 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-06217-w 近日，来自波尔图大学的研究者们在Cell Death Dis.杂志上发表了题为“RhoA balances microglial reactivity and survival during neuroinflammation”的文章，该研究表明在神经炎症期间，最低水平的RhoA活性是连接小胶质细胞炎症反应和存活所必需的。 小胶质细胞是大脑中最大的髓系细胞群。在损伤、疾病或炎症期间，小胶质细胞采取不同的功能状态，主要参与恢复大脑稳态。然而，持续或加剧的小胶质细胞炎症反应可导致脑损伤。动态细胞骨架重组与外部信号驱动的小胶质细胞反应性改变相关，而控制细胞骨架重组的蛋白质，如Rho GTPase RhoA，在损伤、疾病或炎症期间可以很好地改善或调节小胶质细胞的功能状态。 在这里，研究者使用基于多生物传感器的活细胞成像方法和小鼠组织特异性条件基因消融来了解RhoA在小胶质细胞对炎症反应中的作用。研究者发现RhoA活性的降低是小胶质细胞代谢重编程和炎症反应性的绝对要求。然而，如果没有RhoA，炎症会破坏Ca2+和pH稳态，抑制线粒体功能，恶化小胶质细胞坏死，并引发小胶质细胞凋亡。 小胶质细胞对神经炎症的反应需要严格控制RhoA活性 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-06217-w 综上所述，降低RhoA活性(在一定程度上)是实现足够的小胶质细胞炎症能力所必需的。然而，维持最低水平的RhoA活性对于炎症期间小胶质细胞的存活至关重要。因此，微调RhoA信号以平衡小胶质细胞的反应性可能有利于在涉及神经炎症的脑疾病中保持神经元的可塑性。(生物谷 Bioon.com） 参考文献 Renato Socodato et al. Cell Death Dis. RhoA balances microglial reactivity and survival during neuroinflammation. 2023 Oct 20;14(10):690. doi: 10.1038/s41419-023-06217-w.

Using ancestry decomposition techniques an international research team has revealed a deeply divergent ancestry among admixed populations from the Angolan Namib desert. This unique genetic heritage brings the researchers closer to understanding the distribution of genetic variation in the broader region of southern Africa before the spread of food production. Using ancestry decomposition techniques an international research team has revealed a deeply divergent ancestry among admixed populations from the Angolan Namib desert. This unique genetic heritage brings the researchers closer to understanding the distribution of genetic variation in the broader region of southern Africa before the spread of food production. Africa is the birthplace of modern humans and the continent with the highest level of genetic diversity. While ancient DNA studies are revealing some aspects of the genetic structure of Africa before the spread of food production, issues concerning DNA preservation have limited the insights from ancient DNA. Hoping to find clues in modern populations, researchers from a Portuguese-Angolan TwinLab ventured into the Angolan Namib desert -- a remote, multi-ethnic region where different traditions met. "We were able to locate groups which were thought to have disappeared more than 50 years ago," states Jorge Rocha, a population geneticist from Centro de Investigação em Biodiversidade e Recursos Genéticos (CIBIO, University of Porto) who led the fieldwork, together with Angolan anthropologists Samuel and Teresa Aço from the Centro de Estudos do Deserto (CEDO). Among the communities the team encountered are the Kwepe, a pastoral group who used to speak a language known as Kwadi. "Kwadi was a click-language that shared a common ancestor with the Khoe languages spoken by foragers and herders across southern Africa," explains Anne-Maria Fehn, a linguist from CIBIO who participated in the fieldwork and was able to interview what may well be the last two speakers of Kwadi. "Khoe-Kwadi languages have been linked to a prehistoric migration of eastern African pastoralists," adds Rocha, whose research focuses on southern African population history. In addition, the team contacted Bantu-speaking groups that are part of the dominant pastoral tradition of southwest Africa, as well as marginalized groups whose origins have been associated with a foraging tradition, distinct from that of the neighboring Kalahari peoples, and whose original language was supposedly lost. Modern DNA research can complement ancient DNA studies The team's new study shows that the inhabitants of the Angolan Namib are quite divergent from other modern populations but also highly structured among themselves. "In agreement with our previous studies on the maternally-inherited DNA, most genome-wide diversity segregates according to socio-economic status. A lot of our efforts were placed in understanding how much of this local variation and global excentricity was caused by genetic drift -- a random process that disproportionally affects small populations -- and by admixture from vanished populations," says Sandra Oliveira, a researcher at the University of Bern in Switzerland who worked with these populations during her PhD and post-doc studies with Rocha and Mark Stoneking at CIBIO and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig, Germany. The team demonstrated that besides the high impact of genetic drift, which contributed to differences among neighboring groups of different socio-economic status, the descendants of Kwadi speakers and the marginalized communities of the Namib Desert retain a unique Pre-Bantu ancestry that is only found in populations from the Namib desert. Mark Stoneking, who contributed to the earliest genome-wide studies on southern African foragers and participated in this study, says: "Previous studies revealed that foragers from the Kalahari desert descend from an ancestral population who was the first to split from all other extant humans. Our results consistently place the newly identified ancestry within the same ancestral lineage but suggest that the Namib-related ancestry diverged from all other southern African ancestries, followed by a split of northern and southern Kalahari ancestries." With this new information, the researchers could reconstruct the fine-scale histories of contact emerging from the migration of Khoe-Kwadi-speaking pastoralists and Bantu-speaking farmers into southern Africa. Moreover, the study demonstrates that modern DNA research targeting understudied regions of high ethnolinguistic diversity can complement ancient DNA studies in probing the deep genetic structure of the African continent.

Change is coming for software development teams at medical device manufacturers through the Computer Software Assurance (CSA) Act. By Carla Neves, Critical Manufacturing The Computer Software Assurance (CSA) Act of 2022 aims to improve quality and cost-efficiency in validating computer systems for medical device manufacturing. Although it has not been finalized, manufacturers, software developers, and consultants have fully embraced it and are ramping up for implementation. Transitioning to risk-based validation after more than 20 years of document intense compliance will likely dominate medical device software operations for many years to come, as will building out the manufacturing execution system (MES) infrastructure to support it and developing the innovations that the newfound flexibility will drive. The move to CSA The FDA’s primary objective is to increase patient access to high-quality medical devices and help manufacturers deliver those solutions faster while also complying most effectively with FDA laws and regulations. CSA will replace the FDA Computer Software Validation (CSV) guidance that the FDA initially issued in 1997, which tends to cost companies more to validate than to implement. Fearing that this imbalance is discouraging investment in innovation, automation and quality testing, the FDA has revised its guidance around a risk-based model that concentrates validation resources on the areas that are most critical to product quality and patient safety, with hopes that it would free resources for more value-added activities. The CSA guidance also helps companies evaluate their risk factors so they know where to focus. From paper to electronic documents A key value-added activity that CSA strengthens is replacing paper documents with electronic records. This will involve using MES capabilities to generate system logs, audit trails and other software generated data in producing electronic device history records (eDHRs). MES software does this by automatically enforcing compliance through every step of production, ensuring that the right materials are being consumed, that the right people have touched the product, that their certification is right, that materials match designs and quality, and that they are using the right equipment and tools for the job throughout the entire process. This real-time process is the exact opposite of a typical paper-based system, which just records what is happening and depends on a QA worker to review that paper to verify that everything was done correctly. Faster product release CSA speeds product delivery by enabling release by exception, enabling automatic release unless pre-defined critical metrics have not been met. Also helping speed product release, CSA will drive greater use of agile delivery methodologies over traditional waterfall delivery sequences. The move away from waterfall strategies will manifest itself over many years and will require companies to articulate clearly where they are following CSA guidance and where they are still following CSV. Otherwise, auditors might perceive them as cutting corners. Working with vendors and integration partners who have knowledge of both CSV and CSA procedures will be essential for articulating where new guidance is needed to improve product development documentation, how to evaluate the relevance of existing automated tests, and where additional steps might be needed. Leveraging compliance data for performance improvement While one of the biggest advantages of MES software in the medical device space is to enable electronic device history records (eDHRs) for compliance purposes, MES will also help find areas of product improvement. The data it collects for the eDHRs can convert to value by revealing previously hidden problems. It can, for example, reveal sources of micro-downtime or show scrap levels that might never show up in an initial ROI but could add up to substantial savings, uptime, and profitability improvement. In an industry where some medical devices are patented for just a limited amount of time, that could be crucial. Enterprise integration MES software doesn’t stand alone. Companies will be integrating MES software with ERP, machinery, sensors and people to get the full benefit. Software vendors have been improving integration steadily making it as simple as possible, through local and web interfaces, focusing on enabling someone without programming knowledge to use it. In addition to ERP, that integration is also to PLM, QLS, EAM and document management, and many other applications using APIs. Moving to the cloud A recent Gartner study showed that in 2021 about 30 percent of enterprise systems were deployed on the cloud and predicted 90 percent will be on the cloud by 2025. The industry is now going through that deflection point and the timing for a more flexible validation couldn’t be better. The cloud holds the promise of increased collaboration by tearing down organizational and geographic silos. This improves data flow across the supply chain. It will mean improved validation and even faster upgrades. The Association for the Advancement of Medical Instrumentation (AAMI) just issued guidelines for medical device manufacturers who are considering cloud deployment. Not that long ago, having MES software running off-premises was all but unthinkable. It is increasingly possible for companies to deploy secure cloud-based systems that can have huge potential benefits for patients. They can get faster deployment in the cloud without needing to set up hardware on the shop floor or in the IT closet, enabling quick ramp-up as might be needed to produce devices in a medical emergency, such as producing more ventilators to meet COVID-19 pandemic patient needs. On the horizon AI and machine learning are beginning to emerge as well. They can improve outcomes based on deeper data collection and analysis capability. Rather than just analyzing production history they can be more proactive, for example, predicting replacements and repair needs in higher-risk operations. In addition to the technical challenges, change management will be on the mind of many medical device manufacturing software teams over the next few years. They will be challenged to communicate the benefits of the transformation and ensure that all stakeholders understand the goals and benefits of any tools they are using and the implications that CSA can have for quality, efficiency in the plant, and ultimately the health and safety of patients. They will be communicating that CSA is not just an acronym, but represents a real difference in how companies will validate computer system software. What’s next? The hope is that the resources recaptured by streamlining documentation will bring visible benefits quickly. Once companies have their infrastructure in place, they will likely see results quickly, not just in easier compliance and fewer warning letters, but also performance across the board. They will see improved repeatability, fewer mistakes, less rework and redesign, faster time-to-market, improved competitiveness, and lower production costs. And the FDA is betting that patients will enjoy the benefits of innovative diagnostic and treatment devices sooner. Carla Neves is quality manager and medical devices product owner at Critical Manufacturing. Neves holds an electric and electronics engineering degree from the University of Porto and is certified as a scrum master and advanced software test analyst. How to submit a contribution to MDO The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design & Outsourcing or its employees.