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Viral and host factors can shape SARS-CoV-2 evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within individuals. Here, we analysed deep sequencing data from 2,820 SARS-CoV-2 respiratory samples with different viral lineages to describe the patterns of within-host diversity under different conditions, including vaccine-breakthrough infections. In unvaccinated individuals, variant of Concern (VOC) Alpha, Delta, and Omicron respiratory samples were found to have higher within-host diversity and were under neutral to purifying selection at the full genome level compared to non-VOC SARS-CoV-2. Breakthrough infections in 2-dose or 3-dose Comirnaty and CoronaVac vaccinated individuals did not increase levels of non-synonymous mutations and did not change the direction of selection pressure. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 sequence diversification. Our findings suggest that vaccination does not increase exploration of SARS-CoV-2 protein sequence space and may not facilitate emergence of viral variants. There is limited data on within-host SARS-CoV-2 genetic diversity and how it is affected by vaccination. The authors analysed intra-host sequence diversity and found that VOCs may have more sequence variations than non-VOCs and that breakthrough infections in vaccinated individuals do not seem to increase non-silent mutations.

Abstract Background A novel coronavirus of zoonotic origin (2019-nCoV) has recently been identified in patients with acute respiratory disease. This virus is genetically similar to SARS coronavirus and bat SARS-like coronaviruses. The outbreak was initially detected in Wuhan, a major city of China, but has subsequently been detected in other provinces of China. Travel-associated cases have also been reported in a few other countries. Outbreaks in health care workers indicate human-to-human transmission. Molecular tests for rapid detection of this virus are urgently needed for early identification of infected patients. Methods We developed two 1-step quantitative real-time reverse-transcription PCR assays to detect two different regions (ORF1b and N) of the viral genome. The primer and probe sets were designed to react with this novel coronavirus and its closely related viruses, such as SARS coronavirus. These assays were evaluated using a panel of positive and negative controls. In addition, respiratory specimens from two 2019-nCoV-infected patients were tested. Results Using RNA extracted from cells infected by SARS coronavirus as a positive control, these assays were shown to have a dynamic range of at least seven orders of magnitude (2x10−4-2000 TCID50/reaction). Using DNA plasmids as positive standards, the detection limits of these assays were found to be below 10 copies per reaction. All negative control samples were negative in the assays. Samples from two 2019-nCoV-infected patients were positive in the tests. Conclusions The established assays can achieve a rapid detection of 2019n-CoV in human samples, thereby allowing early identification of patients.

Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10 −7 ) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase ( GDA ) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O ( APOO ) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 ( NTRK2 ) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1 , NXPH1 and ANK3 . The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

The Hedgehog (Hh) pathway plays an indispensable role in bone development and genetic activation of the pathway results in medulloblastoma (MB), the most common malignant brain tumor in children. Inhibitors of Hh pathway (such as vismodegib and sonedigib), which are used to treat MB, cause irreversible defects in bone growth in young children. Cholesterol is required for the activation of the Hh pathway, and statins, inhibitors of cholesterol biosynthesis, suppress MB growth by repressing Hh signaling in tumor cells. Here, we investigate the role of cholesterol biosynthesis in the proliferation and Hh signaling in chondrocytes, and examine the bone development in mice after statin treatment. Statins significantly inhibited MB growth in young mice, but caused no defects in bone development. Conditional deletion of NADP steroid dehydrogenase-like (NSDHL), an enzyme necessary for cholesterol biosynthesis, suppressed cholesterol synthesis in chondrocytes, and disrupted the growth plate in mouse femur and tibia, indicating the important function of intracellular cholesterol in bone development. Hh pathway activation and the proliferation of chondrocytes were inhibited by statin treatment in vitro; however, statins did not impair bone growth in vivo due to insufficient penetration into the bone. Our studies reveal a critical role of cholesterol in bone development, and support the utilization of statins for treatment of MB as well as other Hh pathway-associated malignancies.

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p  < 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) ( p  < 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097–7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.

Wild waterfowl serve as a reservoir of some astroviruses. Fecal samples from wild waterfowl collected at Hong Kong's Marshes were tested using pan-astrovirus reverse transcription-PCR. Positive samples underwent subsequent host identification using DNA barcoding. Based on deduced partial sequences, noteworthy samples from three astrovirus groups (mammalian, avian and unclassified astroviruses) were further analyzed by next-generation sequencing. One sample of Avastrovirus 4 clade, MP22-196, had a nearly complete genome identified. The results of ORF2 phylogenetic analysis and genetic distance analysis indicate that Avastrovirus 4 is classified as a distinct subclade within Avastrovirus . MP22-196 has typical astrovirus genome characteristics. The unique characteristics and potential differences of this genome, compared to other avian astrovirus sequences, involve the identification of a modified sgRNA sequence situated near the ORF2 start codon, which precedes the ORF1b stop codon. Additionally, the 3' UTR of MP22-196 is shorter than other avian astroviruses. This study expands our understanding of the Avastrovirus 4 clade.

Methane hydrate is estimated to be present in substantial amounts below deep sea floors. Particular scientific and engineering interests that encourage studies of mechanical behaviour of methane hydrate soils include submarine geohazards, such as the initiation of marine landslides through hydrate dissociation, wellbore stability and estimation of future gas production from wells. To study these problems, a formulation of a multi-physics model of methane hydrate flow coupled to soil deformation is developed. By assuming deformable porous media (soil matrix) that accommodate non-movable but dissociable hydrate, a two-phase flow formulation of water and methane gas is suggested according to Darcy's law and capillary pressure law. A single-phase elastic–perfectly plastic constitutive model for hydrate soil sediments, based on the concept of effective stress, is developed to account for the effect of hydrate saturation on mechanical strength and stiffness. The formulation is incorporated into the explicit scheme of finite-difference code FLAC by solving three boundary value problems in parallel. The code is used to simulate the behaviour of horizontal unsupported and supported wells in hydrate-bearing sediments under different in situ stress conditions during methane hydrate extraction. Axial force, bending moment and well displacements were compared for supported and unsupported wells.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant ( P <0.0057), with PsyCoLaus giving supportive evidence for five SNPs ( P -values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Key Points The Hedgehog (HH) pathway is an important regulator of embryogenesis that has also been implicated in tumour development. As all HH signalling through the canonical pathway requires Smoothened (SMO), small molecules such as GDC-0449, which inhibit SMO function, completely block all HH pathway signalling regardless of the ligand. Drugs based on cyclopamine and other compounds that target SMO have been developed and are currently in Phase I and Phase II clinical trials. Drugs that target other aspects of the HH signalling pathway are also in development. Initial results suggest that SMO inhibitors will prove useful in the treatment of basal cell carcinoma and in the subtype of medulloblastoma that is dependent on HH signalling. It is important to understand how HH inhibitors could be used to treat other cancers, perhaps in combination with other therapies, which do not carry genetic lesions in the HH pathway, but that rely on HH signalling for disease progression. Improved understanding of cancer biology, particularly the interplay among cancer cells and stromal tissues, will help broaden the usefulness of such agents. The identification of reliable biomarkers that indicate patients who are most likely to benefit from HH inhibitors, including non-invasive imaging approaches, is essential. Understanding resistance mechanisms and developing methods to overcome resistance to SMO inhibitors will also be important in the future. The importance of HH pathways during development and studies in mice indicate that SMO inhibitors in children with medulloblastoma will need to be used with care, so that potential effects on skeletal and brain development are avoided. Given the dramatic responses reported in basal cell carcinoma and medulloblastoma in early trials, it is highly likely that SMO inhibitors will ultimately be approved as new therapeutic agents for treating cancer. This should be viewed as a success for basic, broad-based research in developmental biology, as well as cancer research, which laid a strong foundation for this translational opportunity. Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway, and both naturally occurring and synthetic inhibitors of HH signalling show great promise. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies. Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway. Activating mutations in the HH pathway cause a subset of sporadic and familial, skin (basal cell carcinoma) and brain (medulloblastoma) tumours. Furthermore, the growth of many human tumours is supported by HH pathway activity in stromal cells. Naturally occurring and synthetic inhibitors of HH signalling show great promise in animal models and in early clinical studies. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies.