The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. [eabd4570][1], p. [eabd4585][2]; see also p. [404][3] ### INTRODUCTION Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance. ### RATIONALE We established the COVID Human Genetic Effort ([www.covidhge.com][4]) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection. We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life-threatening COVID-19 pneumonia. We considered three loci identified as mutated in patients with life-threatening influenza: TLR3 , IRF7 , and IRF9 . We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF , UNC93B1 , TRAF3 , TBK1 , IRF3 , and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1 , IFNAR2 , STAT1 , and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci. ### RESULTS We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life-threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection ( P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies ( IRF7 and IFNAR1 ) and autosomal-dominant (AD) deficiencies ( TLR3 , UNC93B1 , TICAM1 , TBK1 , IRF3 , IRF7 , IFNAR1 , and IFNAR2 ) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro. ### CONCLUSION At least 3.5% of patients with life-threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection. ![Figure][5] Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life-threatening COVID-19 pneumonia. Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold are encoded by genes with variants that also underlie critical COVID-19 pneumonia. Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection. [1]: /lookup/doi/10.1126/science.abd4570 [2]: /lookup/doi/10.1126/science.abd4585 [3]: /lookup/doi/10.1126/science.abe7591 [4]: https://www.covidhge.com [5]: pending:yes

Tensor linear regression is an important and useful tool for analyzing tensor data. To deal with high dimensionality, CANDECOMP/PARAFAC (CP) low-rank constraints are often imposed on the coefficient tensor parameter in the (penalized) $M$-estimation. However, we show that the corresponding optimization may not be attainable, and when this happens, the estimator is not well-defined. This is closely related to a phenomenon, called CP degeneracy, in low-rank tensor approximation problems. In this article, we provide useful results of CP degeneracy in tensor regression problems. In addition, we provide a general penalized strategy as a solution to overcome CP degeneracy. The asymptotic properties of the resulting estimation are also studied. Numerical experiments are conducted to illustrate our findings.

Directional data consist of observations distributed on a (hyper)sphere, and appear in many applied fields, such as astronomy, ecology, and environmental science. This paper studies both statistical and computational problems of kernel smoothing for directional data. We generalize the classical mean shift algorithm to directional data, which allows us to identify local modes of the directional kernel density estimator (KDE). The statistical convergence rates of the directional KDE and its derivatives are derived, and the problem of mode estimation is examined. We also prove the ascending property of our directional mean shift algorithm and investigate a general problem of gradient ascent on the unit hypersphere. To demonstrate the applicability of our proposed algorithm, we evaluate it as a mode clustering method on both simulated and real-world datasets.

Reinforcement learning has shown great promise for synthesizing realistic human behaviors by learning humanoid control policies from motion capture data. However, it is still very challenging to reproduce sophisticated human skills like ballet dance, or to stably imitate long-term human behaviors with complex transitions. The main difficulty lies in the dynamics mismatch between the humanoid model and real humans. That is, motions of real humans may not be physically possible for the humanoid model. To overcome the dynamics mismatch, we propose a novel approach, residual force control (RFC), that augments a humanoid control policy by adding external residual forces into the action space. During training, the RFC-based policy learns to apply residual forces to the humanoid to compensate for the dynamics mismatch and better imitate the reference motion. Experiments on a wide range of dynamic motions demonstrate that our approach outperforms state-of-the-art methods in terms of convergence speed and the quality of learned motions. Notably, we showcase a physics-based virtual character empowered by RFC that can perform highly agile ballet dance moves such as pirouette, arabesque and jet\'e. Furthermore, we propose a dual-policy control framework, where a kinematic policy and an RFC-based policy work in tandem to synthesize multi-modal infinite-horizon human motions without any task guidance or user input. Our approach is the first humanoid control method that successfully learns from a large-scale human motion dataset (Human3.6M) and generates diverse long-term motions. Code and videos are available at https://www.ye-yuan.com/rfc.

Most real-world knowledge graphs are characterized by a long-tail relation frequency distribution where a significant fraction of relations occurs only a handful of times. This observation has given rise to recent interest in low-shot learning methods that are able to generalize from only a few examples. The existing approaches, however, are tailored to static knowledge graphs and not easily generalized to temporal settings, where data scarcity poses even bigger problems, e.g., due to occurrence of new, previously unseen relations. We address this shortcoming by proposing a one-shot learning framework for link prediction in temporal knowledge graphs. Our proposed method employs a self-attention mechanism to effectively encode temporal interactions between entities, and a network to compute a similarity score between a given query and a (one-shot) example. Our experiments show that the proposed algorithm outperforms the state of the art baselines for two well-studied benchmarks while achieving significantly better performance for sparse relations.

This paper shows how to construct knowledge graphs (KGs) from pre-trained language models (e.g., BERT, GPT-2/3), without human supervision. Popular KGs (e.g, Wikidata, NELL) are built in either a supervised or semi-supervised manner, requiring humans to create knowledge. Recent deep language models automatically acquire knowledge from large-scale corpora via pre-training. The stored knowledge has enabled the language models to improve downstream NLP tasks, e.g., answering questions, and writing code and articles. In this paper, we propose an unsupervised method to cast the knowledge contained within language models into KGs. We show that KGs are constructed with a single forward pass of the pre-trained language models (without fine-tuning) over the corpora. We demonstrate the quality of the constructed KGs by comparing to two KGs (Wikidata, TAC KBP) created by humans. Our KGs also provide open factual knowledge that is new in the existing KGs. Our code and KGs will be made publicly available.

My opinions are my own. An introduction to the harm that ML systems cause and to the power imbalance that exists between ML system developers and ML system participants …and 10 concrete ways for machine learning practitioners to help build fairer ML systems. Image description: Photo of Black Lives Matter protesters in Washington, D.C. -- 2 signs say "Black Lives Matter" and "White Silence is Violence." Machine learning systems are increasingly used as tools of oppression. All too often, they're used in high-stakes processes without participants' consent and with no reasonable opportunity for participants to contest the system's decisions -- like when risk assessment systems are used by child welfare services to identify at-risk children; when a machine learning (or "ML") model decides who sees which online ads for employment, housing, or credit opportunities; or when facial recognition systems are used to surveil neighborhoods where Black and Brown people live. In reality though, machine learning systems reflect the beliefs and biases of those who design and develop them.

The golden age of drone delivery has begun. Did you know drones and their associated functions are a $50 billion industry by 2023? Industry experts are predicting unprecedented use in previously unimaginable applications with deep-learning now powering these drones. Drone delivery services has become an essential tool in fighting the COVID-19 pandemic, helping to create contactless delivery and resilient supply chain services. The retail industry is leading the way in adopting drone delivery services among both consumers and companies.

If you think that the Sahara is covered only by golden dunes and scorched rocks, you aren't alone. In an area of West Africa 30 times larger than Denmark, an international team, led by University of Copenhagen and NASA researchers, has counted over 1.8 billion trees and shrubs. The 1.3 million km2 area covers the western-most portion of the Sahara Desert, the Sahel and what are known as sub-humid zones of West Africa. "We were very surprised to see that quite a few trees actually grow in the Sahara Desert, because up until now, most people thought that virtually none existed. We counted hundreds of millions of trees in the desert alone. Doing so wouldn't have been possible without this technology. Indeed, I think it marks the beginning of a new scientific era," asserts Assistant Professor Martin Brandt of the University of Copenhagen's Department of Geosciences and Natural Resource Management, lead author of the study's scientific article, now published in Nature.

In an area of West Africa 30 times larger than Denmark, an international team, led by University of Copenhagen and NASA researchers, has counted over 1.8 billion trees and shrubs. The 1.3 million km2 area covers the western-most portion of the Sahara Desert, the Sahel and what are known as sub-humid zones of West Africa. "We were very surprised to see that quite a few trees actually grow in the Sahara Desert, because up until now, most people thought that virtually none existed. We counted hundreds of millions of trees in the desert alone. Doing so wouldn't have been possible without this technology. Indeed, I think it marks the beginning of a new scientific era," asserts Assistant Professor Martin Brandt of the University of Copenhagen's Department of Geosciences and Natural Resource Management, lead author of the study's scientific article, now published in Nature.