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Writer｜Rachel Du Layout Designer｜Cecilia Qin Eukaryotic cells contain a macromolecular protease known as the proteasome, which is capable of breaking down proteins that are modified by ubiquitin, but the proteasome can also degrade proteins that lack ubiquitin modification, but the exact mechanism of this process is still unclear. Recently researchers discovered a protein known as Midnolin, which is located in the nucleus and promotes the degradation of many transcriptional regulators through the proteasome, but these transcriptional regulators are not tagged with ubiquitin. Experiments have shown that Midnolin binds tightly to the proteasome and utilizes a mechanism that includes a free beta chain domain to "trap" substrates for catabolism. Thus, the Midnolin-proteasome pathway bypasses the traditional ubiquitination system and achieves selective degradation of many nuclear proteins. In mammals, transcriptional responses triggered by growth factors, neurons, and immune stimuli are mediated by a set of genes known as early genes (IEGs), which encode a family of transcription factors that include Fos, EGR, and NR4A. IEG proteins are activated in virtually all mammalian cells and promote the transcription of late response genes (LRGs), which are essential for the type-specific initial stimulus-response of cells. specific initial stimulus-response is critical. Thus, aberrant IEG expression is associated with cancer, immunodeficiency, and neurological disorders.IEG mRNA accumulates within a short time after initial stimulation, and once translated, its proteins are rapidly degraded to achieve a transient burst of protein expression. Although the mechanism of IEG transcriptional regulation is well understood, the mechanism by which IEG proteins are rapidly and specifically degraded has remained unsolved for many years. Eukaryotic cells rely on the proteasome, a macromolecular protease, to efficiently degrade ubiquitin-tagged proteins. It has been proposed that Fos family proteins may undergo both ubiquitination-dependent and ubiquitin-independent mechanisms upon entry into the proteasome, but the coordination of these molecular processes remains elusive. The study hypothesized the existence of a cellular pathway capable of rapidly degrading c-Fos and other IEG proteins. By utilizing a forward genetic screen, the study aims to reveal the mechanisms that control the degradation of these proteins. The study used a genome-wide CRISPR-Cas9 screen to explore genes that regulate the stability of IEG proteins. The results identified a protein called Midnolin in mammals that promotes proteasomal degradation in IEG proteins (e.g., c-Fos, FosB, EGR1, and NR4A1), which is not dependent on ubiquitination. In addition, Midnolin causes the degradation of a variety of other proteins, including specific transcriptional regulators in the nucleus. multiple stimuli of IEG also activate Midnolin expression, and overexpression of Midnolin induces the target to undergo ubiquitin-independent degradation . In addition, Midnolin uses its "Catch" structural domain to engage the substrate, which is necessary and sufficient for interaction with unstructured regions within the substrate that has the potential to form a β-chain upon binding Midnolin. In addition, Midnolin binds stably to the proteasome via the C-terminal α-helix and promotes the degradation of Catch-bound targets via its N-terminal ubiquitin-like structural domain. Thus, Midnolin contains three conserved structural domains that, by acting synergistically, are able to target a large number of nuclear proteins directly to the proteasome for ubiquitination-independent degradation. The study suggests that the Midnolin-proteasome pathway may be a general mechanism for bypassing the classical ubiquitination system in the selective degradation of nuclear proteins, especially those that are essential for transcription. Midnolin recognizes amphipathic regions within the substrate that have the simplicity to potentially form a β-strand, and thus its degradation determinants may be common structural components. Future studies need to explore how the Midnolin-proteasome pathway is regulated by multiple signals in different cell types to control transcriptional programs.

Author|Asteria Editor|Hecate Ye /Introduction/ Gene therapy is a field of medical research that aims to treat disorders through genetic modification. It involves transferring genetic materials into the cells of patients. In recent years, gene therapy has made significant progress and has been approved for clinical use to treat diseases such as cancer and neurodegenerative disorders. /Strategies/ DNA editing One way to manipulate gene therapy is through DNA editing. There are three main DNA-editing nucleases: zinc-finger nucleases(ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-associated nucleases. ZNFs have two domains: a DNA binding domain that recognizes the DNA in the host genome and a DNA-cleaving domain of Fok1, which is functional as a dimer and cleaves the DNA near the recognition sites. TALENs have Fok1 DNA-cleavage domains like ZNF and transcription activator-like effectors (TALEs)， which are proteins that bind to DNA and manipulate its expression. CRISPR systems use a guide RNA(gRNA) to target a Cas9 protein to target specific sites. gRNAs contain two parts: CRISPR RNA (crRNA) and transactivating CRISPR RNA (tracrRNA). crRNA contains sequences complementary to the DNA sequence that is to be modified and guides Cas9 to the desired location while tracrRNA provides stability. Cas9 modifies DNA by generating double-stranded breaks(DSBs), which are repaired by nonhomologous end-joining (NHEJ). NHEJ is an error-prone DNA repair mechanism that may result in sequence insertions and deletions (INDELs). INDELs typically cause premature termination codons (PTCs), meaning that the protein synthesis process stopped earlier than expected. PTCs would be degraded by nonsense-mediated decay (NMD), a mechanism that recognizes and eliminates mRNAs containing PTCs, thus knocking out the targeted gene. RNA editing RNA-based editing alters RNA, which is transient, resulting in less risk of permanent side effects. The downside of this strategy is that it needs to be injected repeatedly. Antisense oligonucleotides (ASOs), which are synthetic strands of nucleic acids that interfere with the maturation of pre-mRNA to RNA through Watson-Crick base pairing, are used. During maturation, splicing, which is the process in which introns are excluded and exons are joined together, occurs. The exonic enhancers promote exon inclusion and exonic silencers promote exon exclusion. ASOs interfere with this process by including exons that are not usually translated, known as splice inclusion, or the opposite, known as splice exclusion or exon skipping. Cas13d is another tool for RNA editing. It can be packed into a single adeno-associated virus (AAV) for delivery. AAVs are the main non-integrating vectors for in vivo gene therapy, meaning that they deliver the gene into the host cell directly without integrating the DNA into the cell. Cas13 has spacer sequences that are complementary to RNA, and it binds to target RNA, breaking it into small parts and resulting in gene knockdown. /Application/ Alzheimer’s Disease（AD） Alzheimer’s disease is a neurodegenerative disorder characterized by memory loss, difficulties in communication, and impairment of daily functioning. Three genes are targeted for gene-based therapies of AD: APP and microtubule-associated protein tau (MAPT). MAPT encodes tau proteins, which form neurofibrillary tangles in brains, causing symptoms of AD. ASOs decrease MAPT expression and thus prevent tau phosphorylation, thus lowering the levels of tau proteins in cells. APPs are glycoproteins that are cleaved by β-secretases and γ-secretases, proteolytic enzymes in brains, to produce Aβ peptides. One hallmark of AD is the accumulation of plaques, which are primarily made of amyloid β（Aβ）peptides, in brains. Parkinson’s Disease（PD） PD is a neurodegenerative disorder that affects movement control. It has the symptoms of rigidity, tremor, and hypokinesia, which is a decrease in physical activities. One cause of PD is the loss of dopaminergic neurons, neurons that produce and release the neurotransmitter dopamine. Gene therapies have been employed to upregulate dopaminergic signaling in PD. The dopamine synthesis pathway is regulated by three rate-limiting enzymes—GTP cyclohydrolase 1 (GCH1), tyrosine hydroxylase (TH), and aromatic amino acid DOPA decarboxylase (AADC). Gene transfer of GCH1, TH, and AADC into cells enables a high level of conversion of Levodopa precursor of dopamine and medication used in the treatment of PD, into dopamine This therapy is AAV-based and has achieved a modest relief in the symptoms. Disease genes can also serve as gene targets. SMCA, a gene encoding α‐synuclein, acts as a gene target, as mutations in SNCA result in increased levels of α‐synuclein. In rodent models of PD, the knockdown of α‐synuclein through ASO prevents neurodegeneration, and CRISPR-mediated downregulation of α-synuclein has also shown a positive effect. LRRK2 is another disease gene. Variants in LRRK2 increase the risk of developing neurodegenerative disorders, so inhibition of LLRK2 is a viable approach for therapy. However, LLRK2 is also expressed in the lungs, kidneys, and spleen, so global inhibition of LRRK2 is risky. Gene therapy is useful as it specifically inhibits LRRK2 in brains. Intracerebral injection of LRRK2 ASOs is effective in decreasing LRRK2 mRNA levels without obvious side effects. Chimeric antigen receptor (CAR)-T cell therapy CAR-T therapy is a type of immune therapy that uses the power of the patient’s immune system against cancer cells. This therapy involves genetically modifying T cells to express CARs, which are synthetic receptors that are added to T cells to enhance their ability to recognize and attack cancer cells. The first step of CAR-T therapy is to collect the T cells from the patient through blood, then genetically modify the cells to express CAR, forming CAR-T cells. These cells are then cultured and expand in numbers before they are infused into the patient’s body, where they travel and seek out cancer cells. When CARs on the surface of CAR-T cells recognize the antigen in the cancer cells, they attack and destroy the cancer cells. CARs consist of four main domains. The first domain, the extracellular target antigen-binding domain, binds to a particular antigen on the target cell. It consists of variable heavy (VH) and light (VL) chains, linked together by a linker to form a single-chain variable fragment (scFv). The second domain, the hinge region, is a flexible linker that provides stability and allows the scFv domain to bind to the targeted antigen. The length and composition of the hinge region have an impact on CAR functionality. The third domain, the transmembrane domain, anchors CAR to the T cell membrane, and it’s often derived from CD28 or CD8, which are glycoproteins found on the surface of cytotoxic T cells. It ensures that CAR inserts into T cells properly, allowing the extracellular domain to face outward and interact with the target antigen. The fourth domain is the intracellular signaling domain, which is responsible for transmitting signals and activating immune responses when the target antigen is recognized. Most intracellular signaling domain contains proteins called CD3ζ. CD3ζ contains three immunoreceptor tyrosine-based activation motifs (ITAMs), which release signals when it is phosphorylated, activating T cells. /Conclusion/ Though gene therapies are still in the early stages and face several challenges, they provide great hope for countless patients demonstrate huge potential, and hold immense promise for the future of medicine. We hope that more research can be done so that the therapies can be used effectively and can be used to treat more patients.

Author｜Shirley Rao Layout Designer｜Cecilia Qin /Autoimmune Encephalitis/ Autoimmune encephalitis refers to a category of encephalitis mediated by autoimmune mechanisms. Clinically, it manifests as an acute or subacute onset, primarily characterized by deficits in recent memory, abnormal psychomotor behavior, and epileptic seizures. According to the 2014 International League Against Epilepsy (ILAE) practical definition of epilepsy, at this stage, acute provocation or acute symptomatic seizures cannot yet be definitively classified as epilepsy. Based on research findings and clinical practice, experts recommend defining the recovery and post-sequela periods of autoimmune encephalitis as follows: all cerebral symptoms, except for epileptic seizures, such as psychiatric disorders and extrapyramidal symptoms, should have disappeared. Post-encephalitic epilepsy typically results from brain structural damage caused by encephalitis, such as neuronal injury and gliosis, at which point the relevant antibodies no longer have an effect, resulting in negative antibody test results. However, the latent period for this progression remains uncertain and may range from several months to several decades. Therefore, Geis and colleagues recommend that epileptic seizures resembling those of autoimmune encephalitis during the acute phase should not be immediately diagnosed as epilepsy. They suggest conducting follow-ups for at least one year to observe whether non-provoked epileptic seizures persist, before deciding on the continuation of antiepileptic drug (AED) therapy. /Autoimmune Epilepsy/ The concept of Autoimmune Epilepsy has evolved over the years. As far back as 1976, Ettlin and others suggested that epileptic discharges might result from an autoimmune response. In 1995, Barinaga proposed a link between autoimmune hyperactivity and epilepsy. Subsequent research confirmed the association between epilepsy and the immune system, leading to the concept of "immune-mediated epilepsy." In 2002, the International Autoimmunity Congress introduced the term "Autoimmune Epilepsy." Over time, as research advanced, the 2013 revision of the International League Against Epilepsy (ILAE) epilepsy classification defined autoimmune epilepsy as seizures resulting from evidence of autoimmune-mediated central nervous system inflammation. In 2017, a classification of six major etiologies for epilepsy was proposed, with immunological causes being a prominent research focus. The term "Autoimmune Epilepsy" gained widespread usage, yet it remained a subject of debate within the academic community. In July 2020, the ILAE Autoimmune and Inflammation Working Group introduced the term "Acute Symptomatic Seizures Secondary to Autoimmune Encephalitis and Autoimmune-Related Epilepsy." Both autoimmune encephalitis and autoimmune epilepsy are diagnoses at the etiological level. However, epidemiological studies suggest that the proportion of autoimmune epilepsy solely arising from autoimmune encephalitis is relatively low. In other words, the majority of autoimmune epilepsy patients do not have a preceding status of encephalitis, indicating that autoimmune epilepsy can exist independently of autoimmune encephalitis. /Factors Predisposing Autoimmune Encephalitis to Progress into Autoimmune Epilepsy/ Antibodies Currently, the longest known antibodies detected in the cerebrospinal fluid and blood of patients are anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, along with anti-gamma-aminobutyric acid B receptor (GABABR), anti-leucine-rich glioma-inactivated protein 1 (LGI1), and others. Most of these antibodies are surface membrane antibodies. Types of Viral Infections Studies have revealed that various viral infections, such as herpes simplex virus, varicella-zoster virus, and influenza A virus, can trigger NMDAR encephalitis, which is the most common form of autoimmune encephalitis. The potential mechanisms by which viral infections induce autoimmune epilepsy include (1) Structural similarity between viral antigens and neuronal molecules triggering antibody production and subsequent immune responses; (2) Immune reactions leading to direct neuronal damage; (3) Different viral infections may induce the generation of distinct antibodies. Electroencephalography and Imaging Changes Currently, abnormal findings on electroencephalograms (EEG) and neuroimaging studies are considered more valuable in predicting the development of autoimmune epilepsy after autoimmune encephalitis. Autoimmune epilepsy often displays characteristics of a "multifocal, multisource, dynamically evolving" pattern on EEG. Patients with fewer or absent interictal epileptic discharges on EEG are more likely to progress to chronic epilepsy. Various types of autoimmune encephalitis exhibit different functional imaging patterns. For instance, PET imaging in patients with anti-NMDAR encephalitis-associated epilepsy typically reveals a pattern of decreased metabolism, with high metabolism in the frontal and temporal lobes as well as the basal ganglia, and low metabolism in the parieto-occipital lobes. This metabolic pattern may change over time. On the other hand, anti-LGI1 encephalitis-associated epilepsy often shows high metabolism in the medial temporal lobes and bilateral basal ganglia in acute stages (before treatment) and normal or mildly increased metabolism in chronic or recovery stages (after treatment). Diagnostic and Therapeutic Precision Early Immunotherapy in Combination with Antiepileptic Drugs (AEDs) is Crucial for Preventing and Improving the Prognosis of Autoimmune Encephalitis Accompanied by Epileptic Seizure Phenomena." /Conclusion and Perspectives/ Autoimmune encephalitis and autoimmune epilepsy are two diseases diagnosed based on etiology, and they share common features such as anti-neuronal antibodies and overlapping clinical presentations. Moreover, a minority of cases of autoimmune encephalitis may progress to autoimmune epilepsy. Therefore, prompt and careful differentiation between the two conditions and the subsequent selection of appropriate antiepileptic treatment is crucial for improving patient outcomes.

Author丨Li Zhiyuan Layout Designer丨Cecilia Qin BACKGROUND According to the data released by China's National Cancer Center, in 2022 alone, the number of lung cancer cases in China will be 828 thousand and the number of deaths will be 657 thousands, which means that there will be 13 lung cancer patients die every ten minutes. The same situation has also occurred in other countries around the world, including the United States. In the US, approximately 350 people die from lung cancer every day in 2022. Lung cancer tops the list in terms of both mortality and incidence rate. Although many countries have been promoting regular physical examinations and early detection and treatment for cancer. Unfortunately, the 5-year survival rate of resettable lung cancer patients from stage IB to stage IIIA is only 68% to 36%, which means that despite postoperative tumor resection, there are still many lung cancer patients who fail treatment. With the development of tumor treatment technology, there are now various tumour treatment methods, including chemotherapy radiation therapy, surgery, targeted therapy, biological therapy, immunotherapy, and new monoclonal antibody therapy. CHEMOTHERAPY Chemotherapy, one of the most traditional treatment methods, achieves therapeutic goals by using chemotherapy drugs to kill cancer cells. Chemotherapy is more suitable for malignant tumors that are sensitive to chemotherapy, such as SCLC, while the NSCLC mentioned in this article does not belong to the tumor type that is sensitive to chemotherapy, so chemotherapy is not the first choice when treating NSCLC. Meanwhile, as a cytotoxic drug, the occurrence of side effects is inevitable. Digestive system reactions such as nausea and diarrhoea; Bone marrow suppression such as reduction of white blood cells and platelets; Hair loss is also the most common side effect. RADIOTHERAPY AND SURGERY Radiotherapy and surgery: Radiotherapy is a local treatment method that uses radiation to treat tumors. Radiation, including those generated by radioactive isotopes α、β、γ X-rays and various types of X-rays. Approximately 70% of cancer patients require radiation therapy during the treatment process. Like surgery, radiotherapy belongs to local treatment and is only effective for tumors at the treatment site. It is difficult to effectively treat potential metastatic lesions (cancer cells have actually metastasized but cannot be detected and detected clinically due to technical limitations) and cancers that have already undergone clinical metastasis. THE NEW ONE Traditional chemotherapy methods have only improved 5-year survival rates by 5.4% and 5%, respectively, in terms of NSCLC adjuvant therapy and neoadjuvant therapy compared to traditional chemotherapy methods. With the progress of research, axitinib has become the first targeted therapeutic drug approved for adjuvant therapy, with Navulizumab and Atilizumab becoming the first immune drugs approved for neoadjuvant therapy and adjuvant therapy, respectively. At the 2023 AACR conference, AEGEAN, as the first phase III study to announce the results of the "neoadjuvant immunity+surgery+adjuvant immunity" treatment model, provided new ideas for the treatment of NSCLC and is expected to greatly improve patient survival. AEGEAN's study is a randomized, controlled, double-blind, international multicenter phase III clinical trial to evaluate the efficacy and safety of Duvalizumab in a "neoadjuvant immunotherapy + surgical resection + postoperative adjuvant immunotherapy" regimen for resettable IIA IIIB (N2) NSCLC patients without EGFR and ALK mutations. A total of 820 patients were included in the study, randomly assigned 1:1 to the experimental group and the control group (experimental group: neoadjuvant treatment of 1500mg of vallizumab+platinum containing dual drug chemotherapy Q3W, lasting for 4 courses, adjuvant treatment of 1500mg of vallizumab Q4W, lasting for 12 courses; control group: neoadjuvant treatment placebo + chemotherapy, adjuvant treatment placebo). The stratification factors were disease stage (Phase II vs. Phase III) and PD-L1 expression (<1% vs. ≥ 1%). The main endpoints of the study were pCR and EFS, while the key secondary endpoints were MPR, OS, DFS, safety, and quality of life. Through research, it has been found that compared with the use of neoadjuvant chemotherapy alone, the perioperative use of vallizumab combined with neoadjuvant chemotherapy significantly improves the pCR and EFS of resectable NSCLC patients. This proves that the treatment strategy of neoadjuvant immunity+surgery+adjuvant immunity can effectively improve patient survival and treatment success rate. Meanwhile, according to the research results, the proportion of stage III N2 patients has reached 50%, but the treatment effect has not been affected, which proves that this method also has a good control effect on lymph node metastasis. We hope that more and more new treatment strategies can demonstrate higher cure rates and patient survival rates, and we also hope that more PD-L1 can be added to the ranks of tumor treatment drugs.

Author|Rachelle Wu Editor|Hecate Ye Typesetter|Dina Dong Many people may have seen some popular science videos featuring microbes that resemble alien spacecraft, with icosahedral heads, spider-like legs, and a tail pin. These remarkably unique-looking microbes are called bacteriophages, which are a very special type of virus while its host is bacteria, not animal. Their appearance may not seem natural, but what's astonishing is that bacteriophages have been around for 3 billion years, almost appearing alongside bacteria on Earth. They are virtually omnipresent, outnumbering all organic life forms on Earth combined. Although bacteriophages have been around for a long time, it wasn't until 1915 that bacteriophages were discovered by Frederick W. Twort, the Director of the Brown Institute in London. While studying a variant strain of the vaccinia virus used in the smallpox vaccine, Frederick W. Twort accidentally observed that certain bacterial colonies became watery in appearance and could no longer replicate (indicating that the bacteria were killed) Based on this phenomenon, Frederick W. Twort wrote a short article, but due to the outbreak of the First World War and the extensive research and use of penicillin, he did not pursue further investigation. Meanwhile, Canadian medical bacteriologist Felix d'Herelle also discovered this virus capable of halting bacterial growth and named it bacteriophage[2]. Subsequently, he conducted some related research, proving that infecting a normal bacterial colony with the transparent transformation principle kills the bacteria. The transparent entity passes easily through a ceramic filter, can be diluted a million times, and restores its strength, or titer when placed on fresh bacteria. laying the groundwork for further exploration in the future. It is not an exaggeration to say that phages are responsible for a significant portion of deaths on Earth. However, it is important to note that they only kill bacteria, not humans or other organisms. Each day, phages eliminate approximately 40 percent of the bacteria in the ocean [3]. Despite their effectiveness, phages have a crucial limitation: they rely on host bacteria to survive, making mass production and utilization by humans challenging. Phages come in various types, each primarily targeting specific cell types and their variants. When a phage encounters its target bacteria, it punctures the bacterial shell using spines on its tail and injects genetic material, RNA, into the bacterial cell. The phages then undergo rapid multiplication within the host cells. To further aid in bacterial destruction, phages produce a potent enzyme called endolysin, which creates holes in the bacteria's surface. As a result, excessive internal pressure causes the bacteria to rupture, leading to its demise. The phages seize this opportunity to exit and repeat the previous steps. Currently, there is growing interest in phages as a potential avenue for disease treatment. In the past, antibiotics were widely used to combat bacterial infections. However, antibiotics have fixed chemical formulas, and bacteria can develop mechanisms to resist their effects by making mistakes during DNA replication. This resistance has given rise to superbugs, which are highly resistant to antibiotics and pose significant challenges in treatment. It is projected that by 2050, superbugs may surpass cancer as the leading cause of global mortality [3]. Continued research and clinical application of phages in humans offer hope in combating this alarming situation. We are currently engaged in the development of targeted phage therapy for treating infections in humans. While the idea of injecting a large amount of virus into the body may sound risky, humans surprisingly possess immunity against phages. Phages cannot affect humans, as they exclusively target specific bacteria rather than indiscriminately attacking all bacteria like antibiotics. This selective nature allows phages to choose and eliminate specific harmful bacteria while preserving beneficial ones. Now, can bacteria develop immunity against phages? In reality, bacteriophages are viruses that continuously evolve and have been engaged in an evolutionary battle with bacteria for millions of years. They adapt and evolve themselves to combat bacteria effectively. Even if some superbugs have developed resistance against certain phages, they must have simultaneously lost their immunity to antibiotics. In such cases, a combination therapy involving antibiotics and phages can be employed to treat diseases. Consequently, phage therapy represents a long-term strategy in the fight against bacteria, offering benefits beyond the limited scope of antibiotics. There have already been cases where phages have successfully treated diseases that were previously considered incurable by conventional methods. One notable example is the successful treatment of a mycobacterium lung infection, which had become resistant to antibiotics, using bacteriophages. John, a 26-year-old cystic fibrosis patient, had been experiencing recurrent lung infections since childhood, requiring hospitalization several times a year. By the time he reached adulthood, his lung function had deteriorated to 30 percent due to a persistent abscess infection caused by mycobacterium abscessus, despite multiple unsuccessful treatment attempts. Doctors predicted that he would not survive more than a few years without a lung transplant. However, due to the challenging nature of treating mycobacterium infections, which can spread beyond the lungs, no transplant hospital was willing to accept him. In a fortunate turn of events, John was exposed to bacteriophages, and researchers employed genetic engineering techniques to identify several phages capable of targeting the bacteria in his body. In September 2020, John began receiving infusions of phages. After a year, doctors observed a complete recovery in John's condition and arranged for a lung transplant. Currently, John has ceased all treatments for mycobacterium abscesses and has resumed a normal life [4]. While phage therapy is still in the experimental stage and cannot be applied on a large scale, there is hope on the horizon. Pharmaceutical companies have been hesitant to invest billions of dollars in a treatment that has not yet received official approval. However, significant progress has been made, and since 2016, the largest clinical trials involving phages have commenced.[3] This indicates that we may be approaching an era where antibiotics are no longer the primary means of combating bacteria. Phage research is an exceptionally promising field that, when utilized appropriately, has the potential to save numerous lives.

Author | Olivia Editor | Valuri Abstract Neuroscientists at the University of Lausanne and the Wyss Center for Biological and Neuroengineering in Geneva have discovered a new type of cell that is essential for brain function – glutamatergic astrocytes. This cell is intermediate between two common brain cell types, neurons, and glial cells, and is also known as a third cell type. Keywords Glial cells, Neurons, Glutamate, Parkinson's disease (PD), Central Nervous System (CNS) Introduction to the experiment To verify whether astrocytes can also release neurotransmitters like neurons, scientists studied the gene expression of astrocytes. They want to find the necessary mechanisms for the rapid secretion of glutamate, the main neurotransmitter used by neurons. The team used single-cell transcriptomics techniques and localized to different hippocampal loci. Transcripts of vesicular glutamate transporter protein 1 (VGLUT1) are present in this subpopulation of astrocytes. VGLUT1 loads glutamate into synaptic vesicles and facilitates its release across the synaptic gap. Glutamatergic astrocytes promote memory, participate in motor control, and play an important role in the protection of the central nervous system, providing new insights into the role of astrocytes in central nervous system (CNS) disorders. Such as epilepsy, Alzheimer's disease, Parkinson's disease, and others. Experimental Procedure First, the scientists used mice carrying human glial fibrillary acidic protein (GFAP) to verify whether glutamatergic astrocytes can release glutamate at the same rate as synaptic transmission. Next, the scientists prepared tissue-dissociated single-cell suspensions from mouse brain regions and digested the tissues using papain at 37°C, followed by three rounds of abrasive mechanical dissociation using serum pipettes. The researchers used FACS isolation of astrocytes and genomic PCR assays to exclude dead cells. The team used GluSnFR-based in situ and in vivo imaging, which allows visualization of glutamate released from vesicles in brain tissue and in living mice. The scientists then used acute brain slice preparations to prepare acute hippocampal or midbrain slices from transgenic mouse lines or WT mice and used them for patch sequencing, two-photon imaging, and synaptic electrophysiology experiments. The results show that glutamatergic astrocytes respond to selective stimuli with rapid glutamate release, which occurs in spatially separated regions of the cell, like the synapse of a neuron. In addition, the release of glutamate has an effect on synaptic transmission, which the team demonstrated by inhibiting VGLUT expression in these cells. Glutamatergic astrocytes regulate neuronal activity, controlling neuronal communication and excitation levels. Studies on mice have shown that without this functional mechanism, the delayed potential, a neural process in the memory mechanism is impaired, and the mice's memory is impaired as a result. The study also found that such glutamatergic astrocytes are associated with brain diseases. By specifically knocking out VGLUT1 in glutamatergic astrocytes, the team found that this led to increased seizures. Summary In the future, scientists will determine the overall distribution of glutamatergic astrocytes and their all-encompassing role, and better understand why this atypical astrocyte population exists and how its anatomical and functional significance contributes to defined pathologic CNS conditions. The scientists said, "Between neurons and astrocytes, we have discovered a novel cell whose discovery opens up tremendous research prospects. Our next study will explore the potential protective role of this cell against memory impairment in Alzheimer's disease, as well as its role in other regions and pathologies." The scientists wrote at the conclusion of their paper, "Future studies are expected to yield CNS-wide maps that will help to determine the overall distribution of glutamatergic astrocytes and their full range of roles, and to better understand why this atypical astrocyte population exists and the specific ways in which it is anatomically and functionally integrated into CNS system circuits, and whether and how its altered properties contribute to pathologic CNS disorders." The study also shows that glutamatergic astrocytes are also involved in the regulation of motor-controlled brain circuits and could provide new targets for Parkinson's disease. These cells promote memory capacity, and brain control of movement, and suppress seizures. The discovery of this atypical subpopulation of specialized cells has provided scientists with new insights into the complex role of astrocytes in Central Nervous System (CNS) physiology and disease, highlighting a potential therapeutic target.

Author | Icey Layout | Valuri Yang Keywords: Artificial human embryo models, in vitro fertilization technology (IVF), induced pluripotent stem cell(iPSC) "Synthetic human embryos'' (Artificial human embryos) refers to lab-created human embryo models using biotechnology. These embryos are not created through the typical process of fertilizing egg cells with sperm, but are created through other methods, such as using stem cells. In recent years, in vitro artificial embryo technology has attracted widespread attention. Because people's understanding of the early stages of embryonic development is incomplete, and the artificial embryo model provides a valuable model system for studying the early stages of human development. By studying artificial embryos in vitro, scientists can gain a deeper understanding of key events during early embryonic development, such as cell tissue formation and cell-to-cell communication. 01 History and Breakthroughs The history of in vitro embryo research dates back to the early 20th century. The earliest attempts were to culturing egg cells and sperm in vitro, but the success rate was low. With the advancement of cell biotechnology, especially the development of in vitro fertilization technology (IVF), major breakthroughs have been made in in vitro artificial embryo research. Through IVF, sperm and egg cells combine outside the body and form early embryos, which provides the basis for in vitro embryo research. In embryonic research, ethics is an issue of great concern that cannot be ignored. In 1979, the U.S. Department of Health first proposed that experiments on human embryos should not exceed 14 days, because human embryos have not differentiated neural structures and do not have human characteristics before 14 days. Therefore, the "14-day rule" has long been the rule in embryo research. However, the 14-day limit makes it difficult to achieve breakthroughs in experimental results. In May 2021, the International Stem Cell Research Society relaxed the "14-day rule". It is precisely due to the continuous development of science and technology that research after 14 days has been achieved, making more breakthroughs in embryonic research. 02 Methods and Challenges In vitro embryo research requires the use of a variety of technologies and methods, including stem cell culture, three-dimensional tissue engineering, CRISPR gene editing, etc. Among them, the most eye-catching is the application of human pluripotent stem cells (iPSCs). These cells can differentiate into various cell types in vitro after being induced by different media. This characteristic is often called pluripotency. Cell pluripotency is generally divided into two states: naive and primed. Among them, the gene stability of the naive state is better than that of the activated state, and it can form blastocyst chimeras. However, most human pluripotent stem cells are in a state of being activated, so how to stabilize stem cells in a state of being activated is also a problem that needs to be overcome. 03 Ethical and legal challenges In vitro embryo research poses significant ethical dilemmas. One of the most important issues is the legal status of in vitro embryos. Should structures constructed in vitro be considered embryos? Does this involve the origin of human life? In addition, whether there are ethical issues during the research process, such as the destruction, cloning and gene editing of human embryos, requires an international consensus on rules. Future Prospects In vitro embryonic research has great potential. It can be used in disease modeling to help researchers understand abnormalities and disease mechanisms in early embryonic development. In addition, it can also be used for drug testing and toxicity assessment, accelerating the process of new drug development. In the future, in vitro embryo research may also bring more innovations to the fields of reproductive medicine and life sciences.

Author | Rachelle Editor丨Dina Dong In today's society, in high-intensity cities, people's work pressure is increasing day by day. At the same time, sleep problems have troubled for many people. There are many solutions to this problem, such as exercising moderately before going to bed, creating a good sleep environment, taking medication when necessary, and so on. A new study now offers a new opportunity to improve sleep problems – aromatherapy. Aromatherapy is a natural treatment that can be performed with aromatherapy massage, heat compresses or inhalation. It can help the body to be in a balanced state and help improve the mental state.[1]Breathing in pleasant scents during sleep may give a low-effort way to improve brain health and help deter dementia potentially. Olfaction, which is the oldest phylogenetic sensation, is characterized by a unique intimacy with the emotion system.[2] The olfactory pathway has been clarified in some studies.(Figure2) Scientific knowledge with the keywords, “olfaction”, “stress”, and “brain” has been accumulated, some scents cause anxiety and others suppress it. Smell perception may be strongly related to functions of amygdala and hippocampus. After some human and animal studies, smell may be modulated by experience and physical states, and some odors may induce emotional recall. It is pointed out in the article Evaluating the effect of aromatherapy on a stress marker in healthy subjects that aromatherapy with lavender and grapefruit oils can reduce stress by acting on the immune and autonomic nervous systems in healthy volunteers. Neuroscientists found that inhaling odorants while asleep seemed to dramatically enhance a person’s memory over the course of six months in a small experiment involving 23 older adults aged 60 to 85 without memory impairment. In this experiment, participants were divided into two groups. Those in the olfactory enrichment group were provided with an odorant diffuser and seven essential oil odorants (rose, orange, eucalyptus, lemon, peppermint, rosemary, and lavender). In the control group, individuals were also provided with an odorant diffuser , but they were provided with bottles that contained distilled water with an undetectable trace amount of odorant added. During the project, they were asked turn on the odorant diffuser. The scent was released into the air during the night for two hours when they first went to sleep. The scientists gave the participants cognitive tests six months before and six months later. The results showed that those who received aromatherapy had a 226% increase in cognitive performance before and after the experiment. “We found that, compared to controls, ‘enriched’ participants improved in their performance on word-list recall, a key test of verbal learning and memory,”wrote the study authors.[4] Although this investigation was small in size, a professor of neurology and psychology at the University of Pennsylvania in Philadelphia  Jay Gottfried said, the results align with other scientific findings demonstrating a connection between smell and cognition.[4] Study author Dr. Michael Leon, professor of neurobiology and behavior at the University of California, Irvine, said: "When people are endowed with olfactory (related to smell) enrichment, their memory area becomes larger and more functional." "Conversely, when the sense of smell is impaired, the brain's memory centers begin to degenerate."[4] Leon and his colleagues also performed brain imaging and found that in the brains of those who used aromatherapy, the integrity of a brain pathway known as the left hook leaf bundle was better. This pathway connecting the medial temporal lobe necessary for memory and the prefrontal cortex for decision-making becomes less robust with age. The Sleep Foundation notes that while there appears to be no significant difference in sleep quality between the inhaled and control groups, inhaling the scent during sleep may contribute to better rest, which is essential for long-term memory formation and storage.[4] Study authors say they hope the findings will lead to more research into olfactory treatments for memory impairment, and they intend to next examine the impact of inhaling aromas during sleep on people with diagnosed cognitive loss.