Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an ...RNA-DNA hybrid with a displaced non-template DNA strand. We developed RNA-DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA-DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.
Two new SARS-CoV-2 lineages with the N501Y mutation in the receptor-binding domain of the spike protein spread rapidly in the United Kingdom. We estimated that the earlier 501Y lineage without amino ...acid deletion Δ69/Δ70, circulating mainly between early September and mid-November, was 10% (6-13%) more transmissible than the 501N lineage, and the 501Y lineage with amino acid deletion Δ69/Δ70, circulating since late September, was 75% (70-80%) more transmissible than the 501N lineage.
Many of the established positive health benefits of exercise have been documented by historical discoveries in the field of exercise physiology. These investigations often assess limits: the limits ...of performance, or the limits of exercise-induced health benefits. Indeed, several key findings have been informed by studying highly trained athletes, in addition to healthy or unhealthy people. Recent progress has been made in regard to skeletal muscle metabolism and personalized exercise regimes. In this perspective, we review some of the historical milestones of exercise physiology, discuss how these inform contemporary knowledge, and speculate on future questions.
The health effects of exercise are well established, many of which have been uncovered by historical discoveries in exercise physiology. These investigations often assess limits of performance or limits of exercise-induced health benefits. In this perspective, Gabriel and Zierath review historical milestones of exercise physiology and discuss how these inform contemporary knowledge.
The aim of this review is to revisit the meaning of common concepts and frameworks promoted to capture subjective outcomes of patients, the content of their corresponding measurements, and the ...preferred sources of the information of interest. This is important because conceptualizations of ‘health’ and the subject evaluations thereof continue to evolve. Related but distinct concepts like quality of life (QoL), health‐related QoL (HRQoL), functional status, health status, and well‐being are often used indiscriminately to assess clinical impacts of interventions and to influence decisions about patient care and policymaking. The discussion addresses and illustrates the following issues: (1) the required features of effective and valid health‐related concepts; (2) understanding underlying factors that often create confusion about QoL and HRQoL; and (3) how these concepts provide insight into, and promote, health in the context of populations with neurodisability. The hope is to illustrate how a combination of a clear research question, a hypothesis, conceptualization of the required outcomes, and operational definitions of the domains and items of interest, including item mapping, can help to achieve robust methodology and valid findings beyond the required psychometric properties.
What this paper adds
The language, content, and the source of perceived health and life issues are clarified.
Using the same terms for different constructs, or different terms for the same constructs, creates confusion and hinders outcome research.
The challenges of using patient‐reported outcomes in neurodisability are addressed.
What this paper adds
The language, content, and the source of perceived health and life issues are clarified.
Using the same terms for different constructs, or different terms for the same constructs, creates confusion and hinders outcome research.
The challenges of using patient‐reported outcomes in neurodisability are addressed.
Studies of novel coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have reported varying estimates of epidemiological parameters, ...including serial interval distributions-i.e., the time between illness onset in successive cases in a transmission chain-and reproduction numbers. By compiling a line-list database of transmission pairs in mainland China, we show that mean serial intervals of COVID-19 shortened substantially from 7.8 to 2.6 days within a month (9 January to 13 February 2020). This change was driven by enhanced nonpharmaceutical interventions, particularly case isolation. We also show that using real-time estimation of serial intervals allowing for variation over time provides more accurate estimates of reproduction numbers than using conventionally fixed serial interval distributions. These findings could improve our ability to assess transmission dynamics, forecast future incidence, and estimate the impact of control measures.
This article proposes a complementary distributed power amplifier (DPA) using stacked gain cells with multiple input driving signals. The stack multi-drive compensates for the increasing input ...transmission line (TL) and stack losses as frequency increases and results in bandwidth (BW) extension with a flat gain response. The technique simultaneously increases the gain-BW (GBW) product and the output power at high frequencies while maintaining a smaller chip area compared with the conventional DPA design. A broadband active splitter is introduced before the output stage to create two complementary distributed paths which are exploited for AM-AM and AM-PM non-linearity compensation. The CMOS DPA is implemented in 45-nm RFSOI with a core area of 0.31 mm 2 . The amplifier has a 23-dB gain and 108-GHz 3-dB BW from true-dc frequency with no need for external bias tees. The DPA maintains a P1 dB and PSAT over 16.9 and 18.4 dBm, respectively, from dc-to-70 GHz, with a 70-GHz PSAT 3-dB BW. When operated with modulated signals, the DPA provides over 100 Gb/s in both 64-QAM and PAM-4 modulations. To the best of our knowledge, the CMOS DPA reports the highest GBW (1.525 THz), the highest data rate in 64-QAM for carriers up to 59 GHz, and the highest single-ended output swing in PAM-4 modulation.
This article presents fully integrated power amplifiers (PAs) with eight-way low-loss power combining for <inline-formula> <tex-math notation="LaTeX">D </tex-math></inline-formula>-band applications ...in the GlobalFoundries CMOS 45RFSOI process. The eight-way power combining (four-way differential) common source (C.S.) and cascode amplifiers are implemented using four-stage differential PA unit cells as building blocks. The eight-way power combining network is composed of a four-way balun-short-transmission-line (balun-STL) combiner and a conventional quarter wavelength transmission line (QWL TL) combiner. The simulated two-stage eight-way combiner in situ (loaded) ohmic loss is only 1.1-1.4 dB at 130-150 GHz. The eight-way power-combining C.S. amplifier has a small-signal gain of 24 dB at 140 GHz with a 1.2-V supply and a 3-dB bandwidth of 131-150 GHz. The saturated output power (Psat) and output 1-dB compression point (OP 1 dB ) are 16.8-17.5 and 13-14.2 dBm at 130-150 GHz, respectively. The corresponding peak power-added efficiency (PAE) is 11.7%-14.2%. The eight-way power combining cascode amplifier achieves a small-signal gain of 24.8 dB at 135 GHz with a 3-dB bandwidth of 133-148 GHz. The corresponding Psat is 16.3-19 dBm at 125-150 GHz with a peak PAE of 6.5%-12.1%. To the best of our knowledge, these PAs achieve the highest Psat and OP 1 dB at the <inline-formula> <tex-math notation="LaTeX">D </tex-math></inline-formula>-band in CMOS.
The comparative performance of different clinical sampling methods for diagnosis of SARS-CoV-2 infection by RT-PCR among populations with suspected infection remains unclear. This meta-analysis aims ...to systematically compare the diagnostic performance of different clinical specimen collection methods.
In this systematic review and meta-analysis, we systematically searched PubMed, Embase, MEDLINE, Web of Science, medRxiv, bioRxiv, SSRN, and Research Square from Jan 1, 2000, to Nov 16, 2020. We included original clinical studies that examined the performance of nasopharyngeal swabs and any additional respiratory specimens for the diagnosis of SARS-CoV-2 infection among individuals presenting in ambulatory care. Studies without data on paired samples, or those that only examined different samples from confirmed SARS-CoV-2 cases were not useful for examining diagnostic performance of a test and were excluded. Diagnostic performance, including sensitivity, specificity, positive predictive value, and negative predictive value, was examined using random effects models and double arcsine transformation.
Of the 5577 studies identified in our search, 23 studies including 7973 participants with 16 762 respiratory samples were included. Respiratory specimens examined in these studies included 7973 nasopharyngeal swabs, 1622 nasal swabs, 6110 saliva samples, 338 throat swabs, and 719 pooled nasal and throat swabs. Using nasopharyngeal swabs as the gold standard, pooled nasal and throat swabs gave the highest sensitivity of 97% (95% CI 93–100), whereas lower sensitivities were achieved by saliva (85%, 75–93) and nasal swabs (86%, 77–93) and a much lower sensitivity by throat swabs (68%, 35–94). A comparably high positive predictive value was obtained by pooled nasal and throat (97%, 90–100) and nasal swabs (96%, 87–100) and a slightly lower positive predictive value by saliva (93%, 88–97). Throat swabs have the lowest positive predictive value of 75% (95% CI 45–96). Comparably high specificities (range 97–99%) and negative predictive value (range 95–99%) were observed among different clinical specimens. Comparison between health-care-worker collection and self-collection for pooled nasal and throat swabs and nasal swabs showed comparable diagnostic performance. No significant heterogeneity was observed in the analysis of pooled nasal and throat swabs and throat swabs, whereas moderate to substantial heterogeneity (I2 ≥30%) was observed in studies on saliva and nasal swabs.
Our review suggests that, compared with the gold standard of nasopharyngeal swabs, pooled nasal and throat swabs offered the best diagnostic performance of the alternative sampling approaches for diagnosis of SARS-CoV-2 infection in ambulatory care. Saliva and nasal swabs gave comparable and very good diagnostic performance and are clinically acceptable alternative specimen collection methods. Throat swabs gave a much lower sensitivity and positive predictive value and should not be recommended. Self-collection for pooled nasal and throat swabs and nasal swabs was not associated with any significant impairment of diagnostic accuracy. Our results also provide a useful reference framework for the proper interpretation of SARS-CoV-2 testing results using different clinical specimens.
Hong Kong Research Grants Council.
This article presents E- and W-band low-noise amplifiers (LNA) in GlobalFoundries 22-nm CMOS fully depleted silicon-on-insulator (FD-SOI). Both amplifiers employ a three-stage cascode design with ...gain-boosting transformer loads. Design procedures are presented for E- and W-band LNAs for narrowband and wideband applications. The E-band LNA focuses on a high-gain, low-power implementation, and results in a gain and noise figure (NF) of 20 and 4.6 dB at 77 GHz with a 3-dB bandwidth of 12 GHz, and an input P1dB of -27.4 dBm, for a power consumption of 9 mW. The W-band LNA focuses on wideband applications and results in a peak gain of 18.2 dB with a 3-dB bandwidth of 31 GHz, for a power consumption of 16 mW. The LNAs have a high figure-of-merit (FoM) and show very low-power operation in the 70-100 GHz range. Application areas are in phased arrays for 5G with hundreds or thousands of elements, automotive radars at 77 GHz, and sensors at 94 GHz.
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