COVID19 turned out to be one of the deadliest diseases in history. The United States faced a series of new challenges after the Coronavirus spread throughout the world. China is taking advantage of the pandemic to challenge the U.S. global dominance. The main purpose of this article is to analyze the role of the United States in the postpandemic security architecture at a global level. The basic claim of the article is that Washington should reshape U.S. smart power in order to preserve the American global dominance. The article’s claim rests on the assumption that smart power is the most effective instrument of U.S. Foreign Policy in the post-Cold War era. It was U.S. smart power that allowed Washington to maintain its global leadership after the 9/11 attacks. The Coronacrisis will have longterm consequences for the global security architecture. However, this article argues that the Coronavirus pandemic will not change the global order. <<<

Xufeng Chen, Qiao Lu, Hua Zhou, Jia Liu, Bettina Nadorp, Audrey Lasry, Zhengxi Sun, Baoling Lai, Gergely Rona, Jiangyan Zhang, Michael Cammer, Kun Wang, Wafa Al-Santli, Zoe Ciantra, Qianjin Guo, Jia You, Debrup Sengupta, Ahmad Boukhris, Hongbing Zhang, Cheng Liu, Peter Cresswell, Patricia L M Dahia, Michele Pagano, Iannis Aifantis, Jun Wang <<<

Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8 T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers. <<<

Yunli Lai, Xiaofan Zhu, Sheng He, Zirui Dong, Yanqing Tang, Fuben Xu, Yun Chen, Lintao Meng, Yuli Tao, Shang Yi, Jiasun Su, Hongqian Huang, Jingsi Luo, Tak Yeung Leung, Hongwei Wei <<<

To evaluate the performance of noninvasive prenatal screening (NIPS) in the detection of common aneuploidies in a population-based study, a total of 86,262 single pregnancies referred for NIPS were prospectively recruited. Among 86,193 pregnancies with reportable results, follow-up was successfully conducted in 1160 fetuses reported with a high-risk result by NIPS and 82,511 cases (95.7%) with a low-risk result. The screen-positive rate (SPR) of common aneuploidies and sex chromosome abnormalities (SCAs) provided by NIPS were 0.7% (586/83,671) and 0.6% (505/83,671), respectively. The positive predictive values (PPVs) for Trisomy 21, Trisomy 18, Trisomy 13 and SCAs were calculated as 89.7%, 84.0%, 52.6% and 38.0%, respectively. In addition, less rare chromosomal abnormalities, including copy number variants (CNVs), were detected, compared with those reported by NIPS with higher read-depth. Among these rare abnormalities, only 23.2% (13/56) were confirmed by prenatal diagnosis. In total, four common trisomy cases were found to be false negative, resulting in a rate of 0.48/10,000 (4/83,671). In summary, this study conducted in an underdeveloped region with limited support for the new technology development and lack of cost-effective prenatal testing demonstrates the importance of implementing routine aneuploidy screening in the public sector for providing early detection and precise prognostic information. <<<

Spatial normalization or deformation to a standard brain template is routinely used as a key module in various pipelines for the processing of magnetic resonance imaging (MRI) data. Brain templates are often constructed using MRI data from a limited number of subjects. Individual brains show significant variabilities in their morphology; thus, sample sizes and population differences are two key factors that influence brain template construction. To address these influences, we employed two independent groups from the Human Connectome Project (HCP) and the Chinese Human Connectome Project (CHCP) to quantify the impacts of sample sizes and population on brain template construction. We first assessed the effect of sample size on the construction of volumetric brain templates using data subsets from the HCP and CHCP datasets. We applied a voxel-wise index of the deformation variability and a logarithmically transformed Jacobian determinant to quantify the variability associated with the template construction and modeled the brain template variability as a power function of the sample size. At the system level, the frontoparietal control network and dorsal attention network demonstrated higher deformation variability and logged Jacobian determinants, whereas other primary networks showed lower variability. To investigate the population differences, we constructed Caucasian and Chinese standard brain atlases (namely, US200 and CN200). The two demographically matched templates, particularly the language-related areas, exhibited dramatic bilaterally in supramarginal gyri and inferior frontal gyri differences in their deformation variability and logged Jacobian determinant. Using independent data from the HCP and CHCP, we examined the segmentation and registration accuracy and observed significant reduction in the performance of the brain segmentation and registration when the population-mismatched templates were used in the spatial normalization. Our findings provide evidence to support the use of population-matched templates in human brain mapping studies. The US200 and CN200 templates have been released on the Neuroimage Informatics Tools and Resources Clearinghouse (NITRC) website (https://www.nitrc.org/projects/us200_cn200/). <<<

Anthony P Y Liu, Kyle S Smith, Rahul Kumar, Leena Paul, Laure Bihannic, Tong Lin, Kendra K Maass, Kristian W Pajtler, Murali Chintagumpala, Jack M Su, Eric Bouffet, Michael J Fisher, Sridharan Gururangan, Richard Cohn, Tim Hassall, Jordan R Hansford, Paul Klimo, Frederick A Boop, Clinton F Stewart, Julie H Harreld, Thomas E Merchant, Ruth G Tatevossian, Geoffrey Neale, Matthew Lear, Jeffery M Klco, Brent A Orr, David W Ellison, Richard J Gilbertson, Arzu Onar-Thomas, Amar Gajjar, Giles W Robinson, Paul A Northcott <<<

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declines with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma. <<<

Neutrophils are the most abundant leukocyte in humans and provide a critical early line of defense as part of our innate immune system. We perform a comprehensive, genome-wide assessment of the molecular factors critical to proliferation, differentiation, and cell migration in a neutrophil-like cell line. Through the development of multiple migration screen strategies, we specifically probe directed (chemotaxis), undirected (chemokinesis), and 3D amoeboid cell migration in these fast-moving cells. We identify a role for mTORC1 signaling in cell differentiation, which influences neutrophil abundance, survival, and migratory behavior. Across our individual migration screens, we identify genes involved in adhesion-dependent and adhesion-independent cell migration, protein trafficking, and regulation of the actomyosin cytoskeleton. This genome-wide screening strategy, therefore, provides an invaluable approach to the study of neutrophils and provides a resource that will inform future studies of cell migration in these and other rapidly migrating cells. <<<

Wen-Wei Liao, Mobin Asri, Jana Ebler, Daniel Doerr, Marina Haukness, Glenn Hickey, Shuangjia Lu, Julian K Lucas, Jean Monlong, Haley J Abel, Silvia Buonaiuto, Xian H Chang, Haoyu Cheng, Justin Chu, Vincenza Colonna, Jordan M Eizenga, Xiaowen Feng, Christian Fischer, Robert S Fulton, Shilpa Garg, Cristian Groza, Andrea Guarracino, William T Harvey, Simon Heumos, Kerstin Howe, Miten Jain, Tsung-Yu Lu, Charles Markello, Fergal J Martin, Matthew W Mitchell, Katherine M Munson, Moses Njagi Mwaniki, Adam M Novak, Hugh E Olsen, Trevor Pesout, David Porubsky, Pjotr Prins, Jonas A Sibbesen, Jouni Sirén, Chad Tomlinson, Flavia Villani, Mitchell R Vollger, Lucinda L Antonacci-Fulton, Gunjan Baid, Carl A Baker, Anastasiya Belyaeva, Konstantinos Billis, Andrew Carroll, Pi-Chuan Chang, Sarah Cody, Daniel E Cook, Robert M Cook-Deegan, Omar E Cornejo, Mark Diekhans, Peter Ebert, Susan Fairley, Olivier Fedrigo, Adam L Felsenfeld, Giulio Formenti, Adam Frankish, Yan Gao, Nanibaa' A Garrison, Carlos Garcia Giron, Richard E Green, Leanne Haggerty, Kendra Hoekzema, Thibaut Hourlier, Hanlee P Ji, Eimear E Kenny, Barbara A Koenig, Alexey Kolesnikov, Jan O Korbel, Jennifer Kordosky, Sergey Koren, HoJoon Lee, Alexandra P Lewis, Hugo Magalhães, Santiago Marco-Sola, Pierre Marijon, Ann McCartney, Jennifer McDaniel, Jacquelyn Mountcastle, Maria Nattestad, Sergey Nurk, Nathan D Olson, Alice B Popejoy, Daniela Puiu, Mikko Rautiainen, Allison A Regier, Arang Rhie, Samuel Sacco, Ashley D Sanders, Valerie A Schneider, Baergen I Schultz, Kishwar Shafin, Michael W Smith, Heidi J Sofia, Ahmad N Abou Tayoun, Françoise Thibaud-Nissen, Francesca Floriana Tricomi, Justin Wagner, Brian Walenz, Jonathan M D Wood, Aleksey V Zimin, Guillaume Bourque, Mark J P Chaisson, Paul Flicek, Adam M Phillippy, Justin M Zook, Evan E Eichler, David Haussler, Ting Wang, Erich D Jarvis, Karen H Miga, Erik Garrison, Tobias Marschall, Ira M Hall, Heng Li, Benedict Paten <<<

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample. <<<

Protection against lethal ()/ () intra-abdominal infection (IAI)-mediated sepsis can be achieved by a novel form of trained innate immunity (TII) involving Gr-1+ myeloid-derived suppressor cells (MDSCs) that are induced by inoculation (immunization) with low virulence species [i.e., ()] that infiltrate the bone marrow (BM). In contrast, more virulent species (i.e., ), even at sub-lethal inocula, fail to induce similar levels of protection. The purpose of the present study was to test the hypothesis that the level of TII-mediated protection induced by strains inversely correlates with damage in the BM as a reflection of virulence. Mice were immunized by intraperitoneal inoculation with several parental and mutant strains of deficient in virulence factors (hyphal formation and candidalysin production), followed by an intraperitoneal challenge 14 d later and monitored for sepsis and mortality. Whole femur bones were collected 24 h and 13 d after immunization and assessed for BM tissue/cellular damage via ferroptosis and histology. While immunization with standard but not sub-lethal inocula of most wild-type strains resulted in considerable mortality, protection against lethal / IAI challenge varied by strain was usually less than that for , with no differences observed between parental and corresponding mutants. Finally, levels of protection afforded by the strains were inversely correlated with BM tissue damage ( = -0.773). TII-mediated protection against lethal sepsis induced by strain immunization inversely correlates with BM tissue/cellular damage as a reflection of localized virulence. <<<

Rujia Chen, Ning Xiao, Yue Lu, Tianyun Tao, Qianfeng Huang, Shuting Wang, Zhichao Wang, Mingli Chuan, Qing Bu, Zhou Lu, Hanyao Wang, Yanze Su, Yi Ji, Jianheng Ding, Ahmed Gharib, Huixin Liu, Yong Zhou, Shuzhu Tang, Guohua Liang, Honggen Zhang, Chuandeng Yi, Xiaoming Zheng, Zhukuan Cheng, Yang Xu, Pengcheng Li, Chenwu Xu, Jinling Huang, Aihong Li, Zefeng Yang <<<

The role of de novo evolved genes from non-coding sequences in regulating morphological differentiation between species/subspecies remains largely unknown. Here, we show that a rice de novo gene GSE9 contributes to grain shape difference between indica/xian and japonica/geng varieties. GSE9 evolves from a previous non-coding region of wild rice Oryza rufipogon through the acquisition of start codon. This gene is inherited by most japonica varieties, while the original sequence (absence of start codon, gse9) is present in majority of indica varieties. Knockout of GSE9 in japonica varieties leads to slender grains, whereas introgression to indica background results in round grains. Population evolutionary analyses reveal that gse9 and GSE9 are derived from wild rice Or-I and Or-III groups, respectively. Our findings uncover that the de novo GSE9 gene contributes to the genetic and morphological divergence between indica and japonica subspecies, and provide a target for precise manipulation of rice grain shape. <<<

BACKGROUND: Emerged coronavirus disease 2019 (COVID-19) is a pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Disease severity is associated with elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6). Genetic polymorphisms in the regulatory regions of cytokine genes may be associated with differential cytokine production in COVID-19 patients. This study aimed to investigate the association between three potentially functional single-nucleotide polymorphisms (SNPs) in the promoter region of IL-6 and the severity of susceptibility to COVID-19 in an Iranian population.METHODS: In total, 346 individuals (175 patients with severe COVID-19 and 171 patients with mild COVID-19) were recruited for this cohort study. Genomic DNA was extracted from peripheral blood leukocytes of patients to determine the genotypes of three selected SNPs (rs1800795 (-174 G > C), rs1800796 (-572 G > C), and rs1800797 (-597 G > A)) in the promoter region of the IL-6 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.RESULTS: There were no significant differences in the genotype or allele distribution of selected SNPs (rs1800795 (-174 G > C), rs1800796 (-572 G > C), and rs1800797 (-597 G > A)) in the promoter region of the IL-6 gene in patients with severe COVID-19 and patients with mild COVID-19.DISCUSSION: Our study indicated that these SNPs are not associated with COVID-19 severity in the Kurdish population from Kermanshah, Iran. <<<

Pingting Ying, Can Chen, Zequn Lu, Shuoni Chen, Ming Zhang, Yimin Cai, Fuwei Zhang, Jinyu Huang, Linyun Fan, Caibo Ning, Yanmin Li, Wenzhuo Wang, Hui Geng, Yizhuo Liu, Wen Tian, Zhiyong Yang, Jiuyang Liu, Chaoqun Huang, Xiaojun Yang, Bin Xu, Heng Li, Xu Zhu, Ni Li, Bin Li, Yongchang Wei, Ying Zhu, Jianbo Tian, Xiaoping Miao <<<

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology. <<<

Daniel Levine, Syed Asad Rizvi, Sacha Lévy, Nazreen Pallikkavaliyaveetil, Ruiming Wu, Zihe Zheng, Antonio Oliveira Fonseca, Xingyu Chen, Sina Ghadermarzi, Rahul M. Dhodapkar, David van Dijk <<<

AbstractLarge language models like GPT have shown impressive performance on natural language tasks. Here, we present a novel method to directly adapt these pretrained models to a biological context, specifically single-cell transcriptomics, by representing gene expression data as text. Our Cell2Sentence approach converts each cell’s gene expression profile into a sequence of gene names ordered by expression level. We show that these gene sequences, which we term “cell sentences”, can be used to fine-tune causal language models like GPT-2. Critically, we find that natural language pretraining boosts model performance on cell sentence tasks. When fine-tuned on cell sentences, GPT-2 generates biologically valid cells when prompted with a cell type. Conversely, it can also accurately predict cell type labels when prompted with cell sentences. This demonstrates that language models fine-tuned using Cell2Sentence can gain a biological understanding of single-cell data, while retaining their ability to generate text. Our approach provides a simple, adaptable framework to combine natural language and transcriptomics using existing models and libraries. Our code is available at:https://github.com/vandijklab/cell2sentence-ft. <<<

BACKGROUND: Comparative gene expression studies in apes are fundamentally limited by the challenges associated with sampling across different tissues. Here, we used single-cell RNA sequencing of embryoid bodies to collect transcriptomic data from over 70 cell types in three humans and three chimpanzees.RESULTS: We find hundreds of genes whose regulation is conserved across cell types, as well as genes whose regulation likely evolves under directional selection in one or a handful of cell types. Using embryoid bodies from a human-chimpanzee fused cell line, we also infer the proportion of inter-species regulatory differences due to changes in cis and trans elements between the species. Using the cis/trans inference and an analysis of transcription factor binding sites, we identify dozens of transcription factors whose inter-species differences in expression are affecting expression differences between humans and chimpanzees in hundreds of target genes.CONCLUSIONS: Here, we present the most comprehensive dataset of comparative gene expression from humans and chimpanzees to date, including a catalog of regulatory mechanisms associated with inter-species differences. <<<

Reinforcement learning (RL) models have been influential in characterizing human learning and decision making, but few studies apply them to characterizing human spatial navigation and even fewer systematically compare RL models under different navigation requirements. Because RL can characterize one's learning strategies quantitatively and in a continuous manner, and one's consistency of using such strategies, it can provide a novel and important perspective for understanding the marked individual differences in human navigation and disentangle navigation strategies from navigation performance. One-hundred and fourteen participants completed wayfinding tasks in a virtual environment where different phases manipulated navigation requirements. We compared performance of five RL models (3 model-free, 1 model-based and 1 "hybrid") at fitting navigation behaviors in different phases. Supporting implications from prior literature, the hybrid model provided the best fit regardless of navigation requirements, suggesting the majority of participants rely on a blend of model-free (route-following) and model-based (cognitive mapping) learning in such navigation scenarios. Furthermore, consistent with a key prediction, there was a correlation in the hybrid model between the weight on model-based learning (i.e., navigation strategy) and the navigator's exploration vs. exploitation tendency (i.e., consistency of using such navigation strategy), which was modulated by navigation task requirements. Together, we not only show how computational findings from RL align with the spatial navigation literature, but also reveal how the relationship between navigation strategy and a person's consistency using such strategies changes as navigation requirements change. <<<

Zilong Zeng, Jiaying Zhang, Xinyuan Liang, Lianglong Sun, Yihe Zhang, Weiwei Men, Yanpei Wang, Rui Chen, Haibo Zhang, Shuping Tan, Jia-Hong Gao, Shaozheng Qin, Qiqi Tong, Hongjian He, Sha Tao, Qi Dong, Yong He, Tengda Zhao <<<

AbstractSusceptibility artifacts (SAs), which are inevitable for modern diffusion brain MR images with single-shot echo planar imaging (EPI) protocols in wide large-scale neuroimaging datasets, severely hamper the accurate detection of the human brain white matter structure. While several conventional and deep-learning based distortion correction methods have been proposed, the correction quality and model generality of these approaches are still limited. Here, we proposed the SACNet, a flexible SAs correction (SAC) framework for brain diffusion MR images of various phase-encoding EPI protocols based on an unsupervised learning-based registration convolutional neural network. This method could generate smooth diffeomorphic warps with optional neuroanatomy guidance to correct both geometric and intensity distortions of SAs. By employing near 2000 brain scans covering neonatal, child, adult and traveling participants, our SACNet consistently demonstrates state-of-the-art correction performance and effectively eliminates SAs-related multicenter effects compared with existing SAC methods. To facilitate the development of standard SAC tools for future neuroimaging studies, we also created easy-to-use command lines incorporating containerization techniques for quick user deployment. <<<

Anatoly Buchin, Rebecca de Frates, Anirban Nandi, Rusty Mann, Peter Chong, Lindsay Ng, Jeremy Miller, Rebecca Hodge, Brian Kalmbach, Soumita Bose, Ueli Rutishauser, Stephen McConoughey, Ed Lein, Jim Berg, Staci Sorensen, Ryder Gwinn, Christof Koch, Jonathan Ting, Costas A Anastassiou <<<

Temporal lobe epilepsy is the fourth most common neurological disorder, with about 40% of patients not responding to pharmacological treatment. Increased cellular loss is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions, the impact of the disease at the cellular level remains unclear. Here, we show that hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from patients with epilepsy. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume and spine density. Single-nucleus RNA sequencing combined with simulations ascribes the changes to three conductances: BK, Cav2.2, and Kir2.1. In a network model, we show that these changes related to disease progression bring the circuit into a more excitable state, while reversing them produces a less excitable, "early-disease-like" state. <<<

Heiko Schuster, Wenguang Shao, Tobias Weiss, Patrick G A Pedrioli, Patrick Roth, Michael Weller, David S Campbell, Eric W Deutsch, Robert L Moritz, Oliver Planz, Hans-Georg Rammensee, Ruedi Aebersold, Etienne Caron <<<

The large array of peptides presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules is referred to as the MHC class I immunopeptidome. Although the MHC class I immunopeptidome is ubiquitous in mammals and represents a critical component of the immune system, very little is known, in any species, about its composition across most tissues and organs in vivo. We applied mass spectrometry (MS) technologies to draft the first tissue-based atlas of the murine MHC class I immunopeptidome in health. Peptides were extracted from 19 normal tissues from C57BL/6 mice and prepared for MS injections, resulting in a total number of 28,448 high-confidence H2D/K-associated peptides identified and annotated in the atlas. This atlas provides initial qualitative data to explore the tissue-specificity of the immunopeptidome and serves as a guide to identify potential tumor-associated antigens from various cancer models. Our data were shared via PRIDE (PXD008733), SysteMHC Atlas (SYSMHC00018) and SWATH Atlas. We anticipate that this unique dataset will be expanded in the future and will find wide applications in basic and translational immunology. <<<