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The non-coding genome is substantially larger than the protein-coding genome but is largely unexplored by genetic association studies. Here, we performed region-based burden analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and 70,403 non-ALS controls. We identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3′UTR variants significantly enriched in non-ALS genomes, replicated in an independent cohort, and associated with a five-fold reduced risk of developing ALS. Variant IL18RAP 3′UTR reduces mRNA stability and the binding of RNA-binding proteins. Variant IL18RAP 3′UTR further dampens neurotoxicity of human iPSC-derived C9orf72-ALS microglia that depends on NF-κB signaling. Therefore, the variant IL18RAP 3′UTR provides survival advantage for motor neurons co-cultured with C9-ALS microglia. The study reveals direct genetic evidence and therapeutic targets for neuro-inflammation, and emphasizes the importance of non-coding genetic association studies.One Sentence SummaryNon-coding genetic variants in IL-18 receptor 3’UTR decrease ALS risk by modifying IL-18-NF-κB signaling in microglia.

Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95×10−10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.

We consider and compare various exit strategy building blocks and key measures to mitigate the current SARS-CoV-2 pandemic, some already proposed as well as improvements we suggest. Our comparison is based on a computerized simulation integrating accumulated SARS-CoV-2 epidemiological knowledge. Our results stress the importance of immediate on-symptom isolation of suspected cases and household members, and the beneficial effects of prompt testing capacity. Our findings expose significant epidemic-suppression differences among strategies with seemingly similar economic cost stressing the importance of not just the portion of population and business that is released, but also the pattern. The most effective building blocks are the ones that integrate several base strategies - they allow to release large portions of the population while still achieving diminishing viral spread. However, it may come with a price on somewhat more complex schemes. For example, our simulations indicate that a personal isolation of 4 days once every two weeks, for example a long weekend (Fri-Mon) self-isolation once every two weeks, while protecting the 5% most sensitive population would reduce R well below 1 even if ten percent of the population do not follow it. This kind of integrated strategy can be either voluntary or mandatory and enforced. We further simulate the contrasting approach of a stratified population release in a hope to achieve herd immunity, which for the time being seems inferior to other suggested building blocks. Knowing the tradeoff between building blocks could help optimize exit strategies to be more effective and suitable for a particular area or country, while maximizing human life as well as economic value. Given our results, we believe that pandemic can be controlled within a reasonable amount of time and at a reasonable socio-economic burden.

Human gut microbiome composition is shaped by multiple host intrinsic and extrinsic factors, but the relative contribution of host genetic compared to environmental factors remains elusive. Here, we genotyped a cohort of 696 healthy individuals from several distinct ancestral origins and a relatively common environment, and demonstrate that there is no statistically significant association between microbiome composition and ethnicity, single nucleotide polymorphisms (SNPs), or overall genetic similarity, and that only 5 of 211 (2.4%) previously reported microbiome-SNP associations replicate in our cohort. In contrast, we find similarities in the microbiome composition of genetically unrelated individuals who share a household. We define the termbiome-explainabilityas the variance of a host phenotype explained by the microbiome after accounting for the contribution of human genetics. Consistent with our finding that microbiome and host genetics are largely independent, we find significant biome-explainability levels of 16-33% for body mass index (BMI), fasting glucose, high-density lipoprotein (HDL) cholesterol, waist circumference, waist-hip ratio (WHR), and lactose consumption. We further show that several human phenotypes can be predicted substantially more accurately when adding microbiome data to host genetics data, and that the contribution of both data sources to prediction accuracy is largely additive. Overall, our results suggest that human microbiome composition is dominated by environmental factors rather than by host genetics.

In this paper we present a very practical ciphertext-only cryptanalysis of GSM (Global System for Mobile communications) encrypted communication, and various active attacks on the GSM protocols. These attacks can even break into GSM networks that use “unbreakable” ciphers. We first describe a ciphertext-only attack on A5/2 that requires a few dozen milliseconds of encrypted off-the-air cellular conversation and finds the correct key in less than a second on a personal computer. We extend this attack to a (more complex) ciphertext-only attack on A5/1. We then describe new (active) attacks on the protocols of networks that use A5/1, A5/3, or even GPRS (General Packet Radio Service). These attacks exploit flaws in the GSM protocols, and they work whenever the mobile phone supports a weak cipher such as A5/2. We emphasize that these attacks are on the protocols, and are thus applicable whenever the cellular phone supports a weak cipher, for example, they are also applicable for attacking A5/3 networks using the cryptanalysis of A5/1. Unlike previous attacks on GSM that require unrealistic information, like long known-plaintext periods, our attacks are very practical and do not require any knowledge of the content of the conversation. Furthermore, we describe how to fortify the attacks to withstand reception errors. As a result, our attacks allow attackers to tap conversations and decrypt them either in real-time, or at any later time. We present several attack scenarios such as call hijacking, altering of data messages and call theft.

Irregularly-clocked linear feedback shift registers (LFSRs) are commonly used in stream ciphers. We propose to harness the power of conditional estimators for correlation attacks on these ciphers. Conditional estimators compensate for some of the obfuscating effects of the irregular clocking, resulting in a correlation with a considerably higher bias. On GSM's cipher A5/1, a factor two is gained in the correlation bias compared to previous correlation attacks. We mount an attack on A5/1 using conditional estimators and using three weaknesses that we observe in one of A5/1's LFSRs (known as R2). The weaknesses imply a new criterion that should be taken into account by cipher designers. Given 1500–2000 known-frames (about 4.9–9.2 conversation seconds of known keystream), our attack completes within a few tens of seconds to a few minutes on a PC, with a success rate of about 91%. To complete our attack, we present a source of known-keystream in GSM that can provide the keystream for our attack given 3–4 minutes of GSM ciphertext, transforming our attack to a ciphertext-only attack.

In this paper we present a very practical ciphertext-only cryptanalysis of GSM encrypted communication, and various active attacks on the GSM protocols. These attacks can even break into GSM networks that use “unbreakable” ciphers. We describe a ciphertext-only attack on A5/2 that requires a few dozen milliseconds of encrypted off-the-air cellular conversation and finds the correct key in less than a second on a personal computer. We then extend this attack to a (more complex) ciphertext-only attack on A5/1. We describe new attacks on the protocols of networks that use A5/1, A5/3, or even GPRS. These attacks are based on security flaws of the GSM protocols, and work whenever the mobile phone supports A5/2. We emphasize that these attacks are on the protocols, and are thus applicable whenever the cellular phone supports a weak cipher, for instance they are also applicable using the cryptanalysis of A5/1. Unlike previous attacks on GSM that require unrealistic information, like long known plaintext periods, our attacks are very practical and do not require any knowledge of the content of the conversation. These attacks allow attackers to tap conversations and decrypt them either in real-time, or at any later time. We also show active attacks, such as call hijacking, altering of data messages and call theft.

In this paper we ask the question what happens if we replace all the constants in Rijndael, including the replacement of the irreducible polynomial, the coefficients of the MixColumn operation, the affine transformation in the S box, etc. We show that such replacements can create new dual ciphers, which are equivalent to the original in all aspects. We present several such dual ciphers of Rijndael, such as the square of Rijndael, and dual ciphers with the irreducible polynomial replaced by primitive polynomials. We also describe another family of dual ciphers consisting of the logarithms of Rijndael.We then discuss self-dual ciphers, and extend our results to other ciphers.