Hantavirus Infections

汉坦病毒（HTNV）经由啮齿动物传播，其感染小鼠并不致病，但感染人体可引起重症肾综合征出血热（HFRS）。HTNV感染致病机制不清是目前临床防治药物研发的瓶颈。2023年1月10日，空军军医大学张芳琳、雷迎峰、徐志凯、张西京共同通讯在Nature Communications发表题为“Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents”的研究论文，该研究表明鼠源及人源巨噬细胞对HTNV感染反应性的差异决定其对机体炎症的调控作用不同，与HTNV感染致病关系密切。进一步研究显示，感染早期病毒核衣壳蛋白（NP）激活Notch—NF-κB通路使得鼠源/人源巨噬细胞发生M1活化，促进炎症进展；在感染后期，人源巨噬细胞表现为持续活化，而鼠源巨噬细胞可通过Notch—Lnc-ip65—p65轴抑制p65磷酸化，避免M1持续活化而引起过度炎症反应。本研究从长非编码RNA（LncRNA）角度阐释了鼠源/人源巨噬细胞对HTNV反应性差异的分子机制，明晰了鼠源/人源巨噬细胞对HTNV反应性差异发病机制的理论依据，也为HTNV感染提供了一种特殊的治疗策略。汉坦病毒（HTNV）是在世界上分布广、传播途径多、危害极其严重的出血热病毒，感染人体可引起肾综合征出血热（HFRS），以血管内皮损伤及通透性增加为基本病理表现，发病机制与机体过度炎症反应及其产生的细胞因子风暴关系密切。但自然界中的宿主动物，如黑线姬鼠、褐家鼠等啮齿类动物感染HTNV后可以长期携带病毒但不发病，其潜在机制仍有待阐明。巨噬细胞在机体抗病毒免疫应答过程中发挥关键作用，是连接宿主固有和适应性免疫应答的桥梁，也是调控机体炎症反应、维持免疫稳态的重要因素。巨噬细胞在感染过程中存在M1和M2两种可以相互转化的活化模式，前者主要在疾病急性期发挥作用，可促进炎症发生和进展，利于病原清除但加重免疫损伤；后者主要在疾病恢复期/疾病慢性化过程中发挥作用，可抑制炎症反应、促进组织修复但不利于病原清除。本研究探究了巨噬细胞活化模式与HFRS疾病进展的关系，流式细胞术等结果显示HFRS疾病早期，M1活化比例显著增加且与疾病严重程度正相关，人源以TNF-α为核心的促炎巨噬细胞过度活化是HTNV感染所致细胞因子风暴及血管内皮功能紊乱的重要因素，鼠源巨噬细胞的促炎表型（M1）则表现为先激活后抑制。提示鼠源及人源巨噬细胞对于HTNV感染反应性的差异及其不同活化模式对炎症反应的调控作用。文章模式图（图源自Nature Communications）Notch信号是进化中高度保守的信号途径，其调控巨噬细胞活化的机制也逐步被揭示。当Notch受体受到相应配体刺激后，其胞内活化片段NICD从细胞膜内侧释放并进入核内。NICD入核后与转录因子RBP-J相互作用，从而调节基因表达。NF-κB家族中的p65是巨噬细胞活化的关键转录因子，p65-p50组成的异源二聚体活化后可以促进TNF-α、IL-6等炎性细胞因子或趋化因子产生。在感染条件下，巨噬细胞中模式识别信号活化，其通过多种方式激活IκB激酶复合物，IKK-β可促进IκB-α磷酸化并降解，解除IκB-α对p65-p50的抑制作用。本研究发现HTNV感染早期，NICD在胞浆中积累，其与p65和IKK-β相互作用促进p65磷酸化，进而促进M1活化。然而在小鼠中，NICD在感染晚期易位进入细胞核并诱导各种鼠特异性LncRNA表达。其中，Lnc-ip65与NICD竞争结合p65并抑制p65磷酸化，扭转巨噬细胞促炎表型。这些结果为汉坦病毒致病机制提供了新观点，揭示了LncRNA在阻断巨噬细胞多度炎症反应中的免疫功能，为HFRS和其他炎症性疾病提供了潜在的治疗策略。参考文献：Yi Yin Tai et al, Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.add2029. www.science.org/doi/10.1126/scitranslmed.add2029责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

Vancouver, British Columbia--(News - September 18, 2023) - Biocure Technology Inc. (CSE: CURE) ("CURE" or the "Company") announces that it has entered into an exclusive letter agreement dated September 8, 2023 with Atriva Therapeutics GmbH. ("Atriva") whereby the Company will acquire all of the issued and outstanding securities of Atriva (the "Transaction"). The Transaction will be a business combination completed by way of a share exchange, share purchase, amalgamation, arrangement, takeover bid, or other similar form of transaction. Upon the successful completion of the proposed Transaction, it is anticipated that the Company will carry on the business of Atriva (the "Resulting Issuer"). The Transaction constitutes a 'reverse takeover' of the Company. Transaction Summary Pursuant to the Transaction, the Company will issue common shares in its capital ("CURE Shares") to the shareholders in the capital of Atriva ("Atriva Shares") on the basis of a proposed exchange ratio such that, following the closing of the Transaction, on a fully diluted basis, approximately 75% of the securities of the Resulting Issuer will be held by current Atriva securityholders, together with subscribers in a concurrent financing, and approximately 25% of the securities of the Resulting Issuer will be held by current CURE shareholders. No advances to be made by the Company to Atriva are contemplated by the letter agreement. Atriva has agreed to pay to CURE a fee of $15,000 per month as an exclusivity fee pending completion of the Transaction for a minimum period of three months. A finder's fees of US$2,000,000 is payable in connection with the Transaction, to be paid through the issuance of CURE Shares at a deemed price to be determined by the parties but having regard for the terms of a concurrent private placement. The Transaction is subject to a number of terms and conditions, including, but not limited to, the completion of satisfactory due diligence, the parties entering into a definitive agreement with respect to the Transaction on or before 30 November, 2023 (such agreement to include representations, warranties, conditions and covenants typical for a transaction of this nature), the completion of a private placement by Atriva or CURE to raise gross proceeds of at least US$15,000,000 as further described below, the approval of the shareholders of the Company and Atriva, and the approval of the CSE and other applicable regulatory authorities. All dollar figures referenced herein, unless otherwise specified, refer to Canadian dollars. Trading Halt Trading in the CURE Shares has been halted and is expected to remain halted pending the satisfaction of the listing requirements of the CSE. There can be no assurance that trading of CURE shares will resume prior to the completion of the Transaction. Further details concerning the Transaction (including additional financial information) and other matters will be announced if and when a definitive agreement is reached. Information Concerning Atriva Atriva is incorporated under the laws of Germany and is a biopharmaceutical company developing host-cell-targeting antiviral and immunomodulatory therapies. The company was set up by a team of leading scientists in viral disease research and industry experts. Atriva aims to develop novel, highly efficacious and safe therapies for the treatment of severe diseases caused by RNA-viruses with a high unmet medical need and huge cost burden to healthcare systems around the world such as influenza, respiratory syncytial virus infections, dengue fever and hanta virus infections. Atriva's lead product zapnometinib (previously known as ATR-002) is a novel, host-cell-targeting, orally available small molecule drug inhibiting viral replication and rebalancing the body's immune response. Zapnometinib has successfully completed two Phase I clinical trials to demonstrate safety and tolerability in healthy volunteers (NCT04385420 and NCT05555823). A Phase II study (NCT04776044) to evaluate the efficacy and safety of zapnometinib in hospitalized patients with severe COVID-19 obtained approval from Germany`s regulatory authority (BfArM) and generated very promising results. They underpin zapnometinib`s mechanism of action, efficacy against RNA-based virus infections and the safe use in humans. Going forward, Atriva will primarily focus resources on the development of zapnometinib for the treatment of patients hospitalized with severe influenza infections. Due to its mechanism of action with dual benefit - antiviral activity combined with immunomodulation - zapnometinib is uniquely positioned as a highly promising therapeutic candidate for the treatment of severe RNA-virus infections. By treating severe viral infections, Atriva strives to significantly reduce the number of critically sick patients, which would otherwise be referred to ICUs and require more invasive and vastly more expensive treatment options. Consequently, zapnometinib bears the potential to fundamentally improve the outcome of severe virus infections resulting in massive savings for entire societies and their national health care systems. Since inception, Atriva has secured over EUR 40 million in debt and equity investments from various investors and institutions including the European Investment Bank. Further details concerning the Transaction (including additional financial and shareholder information regarding Atriva) and other matters will be announced if and when a definitive agreement is reached. Board of Directors of Resulting Issuer Upon completion of the Transaction, the board of the Resulting Issuer shall be reconstituted to consist of a number of directors, the majority of which will be nominated by Atriva. Details regarding the anticipated directors and officers of the Resulting Issuer will be included in a subsequent release Private Placement Pursuant to the letter agreement, it is a condition of the Transaction that Atriva or CURE complete a private placement for aggregate gross proceeds of at least US$15,000,000 on terms to be determined. Additional details concerning the terms of the private placement will be provided in a subsequent press release. The Resulting Issuer intends to use the net proceeds of the private placement to fund the Transaction, to develop its business and for working capital. This news release does not constitute an offer to sell and is not a solicitation of an offer to buy any securities in the United States. The securities of the Company and BCBC have not been and will not be registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act") or any state securities laws and may not be offered or sold within the United States or to U.S. Persons unless registered under the U.S. Securities Act and applicable state securities laws unless pursuant to an exemption from such registration. Shareholder Meeting Approval for the Transaction will be sought from the Company's shareholders on a date to be determined. Name Change Upon completion of the Transaction, the Company intends to change its name to "Atriva Therapeutics Inc." and the parties expect that the CSE will assign a new trading symbol for the Resulting Issuer. Shares for Debt As an additional re-organizational step for the Transaction, the Company plans to settle approximately $500,000 in debt owed to various parties through the issuance of common shares of the Company at a price of $0.03 per share (the "Settlement Shares"), subject to the approval of the CSE. Portions of the indebtedness are expected to be settled with members of the Company's management team and will constitute a "related party transaction" as defined in MI 61-101. The Settlement Shares will be subject to applicable resale restrictions under securities laws. Corporate Update The Company also reports that Bjorn Cocholovius has resigned from his role as President. The Company wishes Mr. Cocholovius well in his other endeavors. Forward-Looking Statements This news release contains certain "forward looking statements" including, for example, statements relating to the completion of the Transaction and Private Placement and the Resulting Issuer's anticipated share capital. Such forward-looking statements involve risks and uncertainties, both known and unknown. The results or events depicted in these forward-looking statements may differ materially from actual results or events. In addition to other factors and assumptions which may be identified herein, assumptions have been made regarding and are implicit in, among other things: receipt of regulatory approvals, the Company's ability to complete the Transaction and Private Placement, the state of the capital markets, the ability of the Resulting Issuer to successfully manage the risks inherent in pursuing business opportunities in the cannabis industry, and the ability of the Resulting Issuer to obtain qualified staff, equipment and services in a timely and cost efficient manner to develop its business. Any forward-looking statement reflects information available to the Company as of the date of this news release and, except as may be required by applicable securities laws, the Company disclaims any intent or obligation to update any forward-looking statement, whether as a result of new information, future events or results or otherwise. ON BEHALF OF THE BOARD OF DIRECTORS /S/ "Simon Cheng" CEO and Director For further information, please contact: Biocure Technology Inc. Telephone: 604-609-7146, or info@biocuretech.com Neither the Canadian Securities Exchange (the "CSE") nor the Investment Industry Regulatory Organization of Canada) accepts responsibility for the adequacy or accuracy of this release. Completion of the Transaction is subject to a number of conditions, including stock exchange acceptance and shareholder approval. The Transaction cannot close until the required shareholder approval is obtained. There can be no assurance that the Transaction will be completed as proposed or at all. Investors are cautioned that, except as disclosed in the Information Circular and Listing Statement to be prepared in connection with the Transaction, any information released or received with respect to the Transaction may not be accurate or complete and should not be relied upon. Trading in the securities of the Company should be considered highly speculative. The Canadian Securities Exchange has in no way passed upon the merits of the proposed transaction and has neither approved nor disapproved the contents of this press release To view the source version of this press release, please visit

狂犬病疫苗最早于1885年由路易斯•巴斯德在兔脑髓中制备而成，从此开启了狂犬病的防治工作。除使用抗血清之外，疫苗接种仍然是目前最为经济有效且普遍的应对措施。2022年，我国人用狂犬疫苗合计批签发909批次，其中冻干型批签发为781批次（-6%），占比86%；液体型批签发128批次（-10%），占比14%，近年来批签发总量保持平稳。截至2022年12月31日，中国获批上市的人用狂犬病疫苗共有20种，按照培养细胞基质分类来看，其中Vero细胞共13种、地鼠肾细胞共6种、人二倍体细胞共1种；中国正处于临床研究阶段的人用狂犬病疫苗共有24种，其中Vero细胞共13种，人二倍体细胞共8种，鸡胚细胞共3种。同期，中国正处于临床研究阶段的人用狂犬病疫苗共有24种，其中Vero细胞有13种，人二倍体细胞有8种，鸡胚细胞有3种。从在研阶段数据来看，人二倍体狂苗的生产企业增长较快，未来叠加市场认知度也在逐步提升。人类狂犬病疫苗市场可以根据用于培养疫苗的不同细胞基质来划分。不同的细胞基质有不同的特点，因此也需要不同的制造工艺。狂犬疫苗作为我国传统疫苗市场上一个极具代表性的疫苗品种，发展至今，大家也更为关注创新和效率，因此如何利用技术升级支持疫苗工艺的快速开发以及搭建更为安全高效的可放大生产平台，成为近期讨论较多的话题。伴随着行业对于狂犬病疫苗的关注，Cytiva与生物制品圈联合举办的【下一代疫苗开发新思路】系列直播课程将再度聚焦传统疫苗的技术升级，第五期将为大家带来《狂犬疫苗研发进展》相关话题。同时邀请到了长春生物所张颖主任分享国内外狂犬病研究进展及控制措施，并有Cytiva Fast Trak高级上游工艺开发经理杨建军博士分享微载体球转球工艺放大以及灌流培养在狂犬疫苗生产中的应用。4月4日晚19:00，快来报名预约吧。嘉宾介绍张颖 长春生物制品研究所有限责任公司 狂犬室副主任张颖，高级医学生物工程师，硕士研究生学历，现任长春生物制品研究所有限责任公司狂犬室副主任（主持工作），主要从事人用病毒性疫苗的研发、生产及质量管理工作，作为课题主要负责人参与了冻干人用狂犬病疫苗、森林脑炎灭活疫苗及双肾综合征出血热灭活疫苗的工艺开发及质量提升工作。杨建军博士 Cytiva Fast Trak高级上游工艺开发经理杨建军博士毕业于复旦大学，目前是Cytiva Fast Trak工艺开发中心的高级上游工艺开发经理，高级工程师，主要负责上游工艺开发、工艺放大和培训的工作。曾开发过的工艺包括高密度大肠杆菌生产质粒、HEK293T细胞微载体放大培养生产病毒载体、高密度微载体灌流培养生产疫苗、TFF高密度灌流培养生产激酶和抗体等项目。他对多种类型的悬浮细胞和贴壁细胞的放大培养均有丰富经验。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。