Bimodular effects of D614G mutation on the spike glycoprotein of SARS-CoV-2 enhance protein processing,membrane fusion,and viral infectivity

Dear Editor,By the end of June 2020,the pandemic of coronavirus diseases 2019(COVID-19)had resulted in more than 10 million individuals,all over the world,being infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).1 The high contagiousness of SARS-CoV-2 virus was largely attributed to the relatively unique sequence composition in its spike(S)glycoprotein,which is in charge of the host entry by interacting with its cellular receptor angiotensin-converting enzyme 2(ACE2).2,3 The S glycoprotein can be processed into an N terminal S1 fragment that is responsible for receptor binding,and a C terminal S2 fragment that functions to promote membrane fusion.4 SARS-CoV-2 is a type of single-stranded positive-sense ribonucleic acid(RNA)virus,and an increasing number of mutations were identified across the SARS-CoV-2 genome,including the region encoding S glycoprotein.Nevertheless,the functional implications of these mutations remain largely unknown,we here reported the mutation analysis of S gene and a functional exploration of the dominant D614G mutation.

Identification and validation of heterotypic cell-in-cell structure as an adverse prognostic predictor for young patients of resectable pancreatic ductal adenocarcinoma

Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)has a poor prognosis,with an overall 5-year survival rate of less than 10%.Between 20 and 30%of PDAC cases are resectable at diagnosis;however,patients’post-operative survival periods vary widely,irrespective of active therapeutic interventions.1 Therefore,extensive efforts have been made to identify biomarkers that may identify patients with an improved prognosis.Although profound local immune suppression had been implicated in PDAC progression and poor patient survival,a prognostic marker that can directly and functionally read immune evasion in situ is not yet available.

N501Y mutation imparts cross-species transmission of SARS-CoV-2 to mice by enhancing receptor binding

Dear Editor,According to the World Health Organization(WHO),as of March 8,2021,the pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)had infected more than 116 million patients with coronavirus disease 2019(COVID-19)(https://covid19.who.int).The high infectivity of SARS-CoV-2 is largely attributable to the unique sequence composition of its spike(S)glycoprotein.

The virological impacts of SARS-CoV-2 D614G mutation

The coronavirus diseases 2019(COVID-19)caused by the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 has caused more than 140 million infections worldwide by the end of April 2021.As an enveloped single-stranded positive-sense RNA virus,SARS-CoV-2 underwent constant evolution that produced novel variants carrying mutation conferring fitness advantages.The current prevalent D614G variant,with glycine substituted for aspartic acid at position 614 in the spike glycoprotein,is one of such variants that became the main circulating strain worldwide in a short period of time.Over the past year,intensive studies from all over the world had defined the epidemiological characteristics of this highly contagious variant and revealed the underlying mechanisms.This review aims at presenting an overall picture of the impacts of D614G mutation on virus transmission,elucidating the underlying mechanisms of D614G in virus pathogenicity,and providing insights into the development of effective therapeutics.

Molecular mechanisms underlying cell-in-cell formation:core machineries and beyond

Although cell-in-cell structures(CICs),with one or more cells present inside another cell,had been identified for a century,it was not until recent years that scientists started to uncover their pivotal roles in multiple biological processes,primarily via mediating the death of internalized cells.Meanwhile,considerable progresses were made on deciphering the mechanisms underlying their formation based on different models.Entosis was one of the best investigated CIC models,where cell internalization was coordinately driven by adherens junction and contractile ac-tomyosin,the two spatially polarized and complementary core elements that were coupled by mechanical ring,a recently identified core element.Meanwhile,an expanding group of factors were found capable of regulating CIC formation by targeting these core elements.The elucidation of the molecular machinery controlling CIC formation enables synthetic engineering of cells used for clinical and research purposes。

AIM-CICs: an automatic identification method for cell-in-cell structures based on convolutional neural network

Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis rely strictly on the identification of cell-in-cell structures (CICs), a unique morphological readout that can only be quantified manually at present. Moreover, the manual CIC quantification is generally over-simplified as CIC counts, which represents a major hurdle against profound mechanistic investigations. In this study, we take advantage of artificial intelligence technology to develop an automatic identification method for CICs (AIM-CICs), which performs comprehensive CIC analysis in an automated and efficient way. The AIM-CICs, developed on the algorithm of convolutional neural network, can not only differentiate between CICs and non-CICs (the area under the receiver operating characteristic curve (AUC) > 0.99), but also accurately categorize CICs into five subclasses based on CIC stages and cell number involved (AUC > 0.97 for all subclasses). The application of AIM-CICs would systemically fuel research on CIC-mediated cell death, such as high-throughput screening.