畢竟現在我是研究生了，為了督促自己養成定期瀏覽學術期刊的習慣，我決定把看到的東西都寫下來做個摘要總結和點評，之前上文獻討論課我會手寫記錄。上小學有做數學小報，以前還有積累作文素材和好詞佳句，現在也是一樣。在哈佛讀碩的第一個學期還有個感悟就是科學要學會與人分享成果，傳播知識。有個教授大概說了這樣一句話，如果你說你做的是HIV有關的研究，別人會覺得這很有意義因為大家都知道HIV, 但其實你可能只是沾了HIV的名氣。真正厲害的就是能把自己的研究用通俗的方式傳播給大眾。做這個還是挺麻煩的，自己還學藝不精，不知道能堅持做多久😅，但是文章肯定是會看的。
本次內容摘自上周四發布的 Nature Volume 588 Issue 7839（有年終總結的感覺）和新鮮出爐的2021一月刊 Trends in Molecular Medicine, Trends in Immunology，封面圖就是這三門期刊在這三期的封面組合圖
SARS-CoV-2 wreaked havoc across the globe-- everyone's in the same boat
「What is the best drug to treat COVID-19? 在臨床治療中作者呼籲使用更多的隨機性的藥物治療和對照實驗 （採用兩種及以上的藥物組合）
The authors call for randomized controlled clinical trials which is more informative to "answer questions regarding toxicity and efficacy beyond standard of care". The single-arm study gives one type of antiviral drug for patients could tell dosage, duration and appropriate endpoints. Suggested drugs involve antiviral, immunomodulatory and antimalarial ones, but it is still unclear which one could be effective for mild or severe COVID-19 patients. Therefore, it is necessary to carry out randomized and controlled studies with assessment of viral loads during the trials (Ottaviani and Stebbing, 2021).
Combining antivirals and immunoodulators 免疫應答的雙刃劍
Cytokine storm is a major hurdle when the first immune response is defective and the disease worsens, which promotes inflammation. All cell types are able to produce IFNα, but plasmacytoid dendritic cells (pDCs) can rapidly produce large amounts of this cytokine (Lande and Gilliet, 2010)" 本文總結了一些antiviral drugs, 從病毒整個life cycle的各個環節逐一擊破。antiviral state的重要細胞因子之一是type 1 IFN,但也會導致cytokine storm+炎症,因此anti-inflammatory的timing也是很重要的。It also explores the kinetics between viral load/level of inflammatory cytokines and severity of disease。Overproduction of cytokines are more likely to cause severe/critical patients.
In the end, authors summarize the rational treatment against COVID-19: importance of early diagnosis, quick response to IFNa/b supplement and blocking the cytokine storm at the later stage. (Feuillet et al., 2021)
More about IFN:上學期期末老師讓我們做poster可選擇一個感興趣的COVID的話題，我就對IFN therapies比較感興趣，因為不同研究對它的結果有分歧，這裡我展示一下我自己做的結果（本來是會有個正式的同學之間的交流展示的活動，但因為疫情取消了。score 19/20, 所以肯定有不足的地方）。我的主要結論是跟上面的也差不多。總之就是很奇怪有的人感染後會分泌不夠IFN,但是如果IFN失控了就會有更嚴重的後果。
Appload T cells for their efforts to fight against SARS-CoV-2 infection
T細胞是我最喜歡的免疫細胞，細分種類繁多。"T Cells: Warriors of SARS-CoV-2 Infection" (Cadia, et al, 2021)這篇文章有很詳細的對各種T cell function的總結，值得收藏
明年一雜誌新政策
"A new pubishing mode: publish, then reivew": The elife journal announced a new policy which will come into effect after next July. All of their reviewed and published paper will be posted on a preprint server first.
Although the preprint server is commonly used now, I am not sure if this is a trend for a journal to publish paper after receiving public review. In this way, the paper can receive worldwide reviews and improve their manuscripts, but may also extend their time to publish paper on a formal journal. For teams who compete to release their results, they may not want to choose this way.
展望2021
"Ways to look after yourself and others in 2021 given by climate scientist Kim Cobb" by Vriginia Gewin on Nature
-create boundaries: separate personal and professional time for people working remotely (其實我決定這可能只針對工作狂吧)
-enhance virtual interactions, such as video-conferencing software Zoom
-advocate for remote work, like communicating with supervisors about work schedules
-support team well-being: students (like me, hhh) may work in the lab to please their supervisors not caring the risk of being infected, so PI should prioritize lab members' health
-track pandemic career effects, concerning the detrimental career setbacks
-spead knowledge (I believe this has been well-done this year, but we should be careful of those fake ones)
兩項有趣的研究/一句話總結：
1）circular extrachromosomal DNA amplification as the initation of cancer can be derived from chromothripsis (clustered chromosomal rearragements)oncogene/癌腫崛起的起源是大規模局部的基因重組的破壞性事件，這裡涉及到了一個我比較陌生的概念就是chromothripsis and forming micronuclei是一種突然的孤立的遺傳物質洗牌現象
2）Strategy of the month | Trends in Moelcular Medicine
"DNA damage repair deficiency and synthetic leathality for cancer treatment" (Burdak-Rothkamm and Rothkamm, 2021)
Block PARP to prevent DNA damage repair pathways in cancer cells which are homologous recombinatio repair deficency.
癌腫治療：阻礙腫瘤細胞重的DNA破損修復
吃辣會增強造血幹細胞從骨髓的流動性？
降脂利器可以幫助immune checkpoint therapy?
肥胖會對腫瘤附近的免疫細胞有不好的影響！！(High-fat diet-induced obseity impairs CD8+T cells infiltration to tumor cells because they don't uptake fat)（這是發表在cell的，但出現在nature的highlight中，而且還是本校的某大佬團隊發表的）
前兩篇Latest research 詳情總結：
1）標題：Nociceptive nerves regulate haematopoeitic stem cell (HSC) mobilization
器官裡負責傷害感受器的神經細胞可產生神經遞質CGRP， 激活HSC的CALCRL-RAMP1 受體，使其流出骨髓(BM)。機製圖見下（CSF實驗中是直接體內注射到小鼠，但是我不知道它到底是直接影響了神經細胞還是HSC）
-研究意義：blood cancer 治療用autologous stem cell transplanation，需要搜集HSC在血液中。HSC能夠從骨髓裡流進出，遍布在周遭器官組織中，幫助局部免疫。diseased BM會降低HSC在其他地方的yield。還有就是加深對HSC 流動性的理解，與nerons的細胞交互。HSC除了migration還有其他三個fate choices,分別是apoptosis, self-renewal和differentiation。Nature上面還有一篇寫得不錯的針對本文的評論
-主要方法：
fig. 1).denervation in mice: 通過藥物(RTX, 6OHDA) 或者用cre-inducible tissue-speicifc KO mice drug treated denervation in mice來看HSC在spleen/blood的數量改變(註：我對神經不太熟悉，這裡針對了sympathetic 和sensory/noiceptor 兩種nerons進行了dual denervation）
fig. 2). transfuse blood等等來看denervation後HSC moblization
fig. 3). colony-forming of migrated stem progenitor, blood stransfusion and transwell assay 來證明缺失Ramp1會降低HSC migration
fig. 4). 對Ramp1-/- mice的HSC進行RNA sequencing,發現
Gαs–adenylyl cyclase–cAMP pathways有下降, 外加其他驗證
給小鼠餵capsaicin-containing diet（模擬人吃辣），刺激nociceptor 來增強mobilization
2) -標題：Inhibition of PCSK9 potentiates immune checkpoint therapy
-研究蛋白：PCSK9 (Proprotein convertase subtilisin/kexin type 9)
-假說與理由：PCSK9 downregulates diverse cell-surface proteins (e.g. LDLR). It can also recycle and degrad MHC I from the cell surface and interfere
-背景補充：MHC I is expressed on all nucleated cells to present peptides （self or foreign) for CD8 T cells to recognize.
-部分方法與結果總結：
fig1. KO PCSK9 by CRSPR in different cancer cell lines, decreased tumor growth in syngeneic mice (WT?), but no difference in immunodeficient mice, indicating the necessity of immune cells.
fig2.Antibody blocking PCSK9 can retard the growth of anti-PD1 resistant tumors
fig3. KO PCSK9之後看各種T cells和NK 等 inflitration into tumor,主要用flow cytometry; analyze TCR repertoire to see the diversity of mature T cells; OT-1 transgenic mouse model shows an increase of CD8 T cells ability to kill OVA-transduced PCSK9-deficient melanoma cells in vitro.
fig4. 機制來啦：PCSK9 deficiency 會升高H2-Kb MHC I, 同時OE MHC I + anti-PD1 ,明顯比control更能降低tumor growth(促進了CD8 T cells activation and killing ability)
具體PCSK9是怎麼影響MHC I的呢，之前有說cholesterol levels may affect MHC I recyclin（rule out LDLR as key cholesterol regulator, downstream target of PCSK9去影響MHC I的可能性）。OE-PCSK9，more H2-K1 in lysosome fraction by WB.
小結：PCSK9單抗之前應用於治療心血管疾病可幹擾LDLR的再循環，本文探討它對MHC I的循環作用，有創新性，期待它與anti-PD1的結合使用。但是對cholesterol metabolism會不會有影響呢，還有我不是很清楚PCSK9的表達水平在不同細胞/腫瘤中會不會不太一樣，是否運用會有局限性。
Reference:
Asteroid treasure, COVID vaccine and public peer review. (2020, December 23). Retrieved December 29, 2020, from https://www.nature.com/articles/d41586-020-03553-1
de Candia, P., Prattichizzo, F., Garavelli, S., & Matarese, G. (2020). T Cells: Warriors of SARS-CoV-2 Infection. Trends in immunology.
Gao, X., Zhang, D., Xu, C., Li, H., Caron, K. M., & Frenette, P. S. (2020). Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature, 1-6.
Gewin, V., 2020. Ways To Look After Yourself And Others In 2021. [online] Doi.org. Available at: <https://doi.org/10.1038/d41586-020-03558-w> [Accessed 29 December 2020].
Liu, X., Bao, X., Hu, M., Chang, H., Jiao, M., Cheng, J., ... & Li, C. Y. (2020). Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature, 1-6.
Ottaviani, S., & Stebbing, J. (2020). What is the best drug to treat COVID-19? The need for randomized controlled trials. Med.
Ringel, A. E., Drijvers, J. M., Baker, G. J., Catozzi, A., García-Cañaveras, J. C., Gassaway, B. M., ... & Yao, C. H. (2020). Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell.
部分圖片來源於網絡
結尾寄語
2021又是需要全力以赴的一年，希望生活能早日恢復到正常的秩序，期待mask-free到來的一天！