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The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.

The experience of anxiety is central to the development of chronic pain. Music listening has been previously shown to exert analgesic effects. Here we tested if an active engagement in music making is more beneficial than music listening in terms of anxiety and pain levels during physical activity that is often avoided in patients with chronic pain. We applied a music feedback paradigm that combines music making and sports exercise, and which has been previously shown to enhance mood. We explored this method as an intervention to potentially reduce anxiety in a group of patients with chronic pain (N = 24, 20 female and 4 men; age range 34–64, M = 51.67, SD = 6.84) and with various anxiety levels. All participants performed two conditions: one condition, Jymmin, where exercise equipment was modified with music feedback so that it could be played like musical instruments by groups of three. Second, a conventional workout condition where groups of three performed exercise on the same devices but where they listened to the same type of music passively. Participants' levels of anxiety, mood, pain and self-efficacy were assessed with standardized psychological questionnaires before the experiment and after each condition. Results demonstrate that exercise with musical feedback reduced anxiety values in patients with chronic pain significantly as compared to conventional workout with passive music listening. There were no significant overall changes in pain, but patients with greater anxiety levels compared to those with moderate anxiety levels were observed to potentially benefit more from the music feedback intervention in terms of alleviation of pain. Furthermore, it was observed that patients during Jymmin more strongly perceived motivation through others. The observed diminishing effects of Jymmin on anxiety have a high clinical relevance, and in a longer term the therapeutic application could help to break the Anxiety Loop of Pain, reducing chronic pain. The intervention method, however, also has immediate benefits to chronic pain rehabilitation, increasing the motivation to work out, and facilitating social bonding.

Optical engineering 61(09), 095103 (2022). doi:10.1117/1.OE.61.9.095103, Published by SPIE, Bellingham, Wash.

While previous research has conclusively established that children with higher cognitive ability and those originating from advantaged socioeconomic status (SES) backgrounds have better educational outcomes, the interplay between the influences of cognitive ability and social origin has been largely overlooked. The influence of cognitive ability might be weaker in high-SES families as a result of resource compensation, and stronger in high-SES families owing to resource multiplication. We investigate these mechanisms while taking into account the possibility that the association between cognitive ability and educational attainment might be partly spurious due to unobserved genetic and environmental influences. We do so by analysing a large sample of twins from the German TwinLife study (Npairs = 2,190). Our results show that the association between cognitive ability and educational attainment is to a large extent confounded by genetic and shared environmental factors. If this is not considered, and this is the case in most previous studies, high-SES parents seem to compensate for the lower cognitive ability of their children. However, when we consider the genetic and shared environmental confounding, the resource compensation effect becomes non-significant.

Additional file 10: Figure S7. Cellular back mapping identifies co-localizing protein populations at extranuclear DNA segments. A. images shown in Fig. 4, all channels. B. Analysis of KDM6A TPR and NPM1: Cellular back mapping identifies a colocalizing population (orange) and free KDM6A TPR (green) and NPM1 (red) at cytoplasmic DNA segments. C. scatterplot analysis and cellular back mapping of KDM6A variants and DAPI as indicator of KDM6A-DNA complexes. In KDM6A WT scatterplot we identified four populations: 1 = cytoplasmic KDM6A (without DAPI) and 4 = DAPI (without KDM6A), as well as, populations #2 and #3, which resemble different ratios of KDM6A-DNA complexes. Population 2 is located at the lamina and in nucleolar puncta, and population 3 is located within the nucleoplasm. Substitution variant T726K shows minor differences in populations #2 and #4, as the lamina in #2 is less clearly visible, but strongly enriched in population #4. Contour scatterplot of JmjC or TPR with DAPI identified only three populations, with population #1 being absent. Back mapping clearly indicates compartment-wise localization of different DAPI-KDM6A JmjC or TPR compositions.

Additional file 5: Figure S2. Activity assay and data analysis. In this section, we describe our data analysis workflow. A. delta (grey shaded area) in fluorescence emission spectrum of eGFP-KDM6A WT lysate before incubation and after incubation with GFP-trap dynabeads. For data analysis, the amount of pulled fluorescent protein was determined by subtracting the eGFP fluorescence emission (470 nm excitation) after incubation with GFP-trap dynabeads from eGFP fluorescence emission before incubation with eGFP-trap dynabeads. Fluorescence intensities in the range of 500–530 nm were integrated subsequently (later referred to as integrated fluorescence). B. Maximum-normalized spectra obtained from crude cell lysate of eGFP, eGFP-KDM6A WT or eGFP-KDM6A Q1133A samples. All fluorescence emission spectra of the substitution variants had a similar profile between 500 and 530 nm. This was used to compare the amount of protein for each variant. Q1133A variant is shown exemplarily for all other substitution variants. C. Fluorescence emission spectra of WT and ΔJmjC. The high signal of ΔJmjC towards the blue end of the spectrum is due to scatter, which could indicate protein instability under the given (low salt) buffer conditions. D. 1–238 ng demethylated product (H3K27me2 peptide, MW = 2945.5 g/mol) was obtained from at least nine data points from three independent experiments, each in triplicates and fitted with a four parameters logistic regression (4-PL) according to Eq. 1: y = d + a − d 1 + x c b $$ \mathrm{y}=\mathrm{d}+\frac{\mathrm{a}-\mathrm{d}}{1+{\left(\frac{\mathrm{x}}{\mathrm{c}}\right)}^{\mathrm{b}}} $$ (1) with y = assay readout absorption, x = amount of product in A., amount of KDM6A species, either by fluorescence in B. or amount of protein in D., a = background signal, d = maximum signal, b = slope factor, c = c50, x-value at half maximum y.The following fit results were obtained: a = 0.29, b = 1.27, d = 1.73 and c = 62.4 ng. E. The amount of protein was plotted against absorption (shown for KDM6A WT) and fitted accordingly with 4-PL, with c being the only open parameter. c50 for WT was determined with 518,000 +/− 56,000 AU. To correct for background and maximum signal fluctuation between experiments, they were normalized to the values obtained from the product curve fit (a = 0.29, d = 1.73). F. A defined amount of recombinant eGFP (27 kDa) was used to convert the x-axis from fluorescent signal to the amount of protein. The linear dependency was used to calculate the amount of eGFP-KDM6A (181 kDa) per fluorescent unit. The molar integrated fluorescence (500–530 nm) from emission spectra for recombinant eGFP (MW = 26.9 kDa) was determined as 2.34E+ 18 AU/mol from the relation 1 ng eGFP = 86,900 [AU]. Therefore, 1 ng eGFP-KDM6A WT would yield an integrated fluorescence signal of 1.29E+ 03 AU. G. Data from E. and F. were used to transform the x-Axis with the fluorescent signal into the amount of KDM6A protein,. Approximated from D., the respective c50 always corresponded to 62.4 product. This correlation was used to calculate the specific activity for each variant. Given the fixed time of 240 min per assay, the specific activity under these conditions was calculated. The c50 for all available substitution variants was obtained in the same manner, fixing all parameters except c, using it as a relative measure of activity. At least four independent triplicate measurements were obtained for each substitution variant. H. absorption for truncated variants, three repeats with triplicates each. Since the truncated variants showed an unusual spectrum with a high scatter fraction at lower wavelengths (see C.), a quantification was impossible. Therefore, we qualitatively confirmed, that all truncated variants with a JmjC domain are catalytically active (green boxes) and those without JmjC domain are catalytically dead (red boxes). The distribution of the signal over the background is an evidence for activity in all truncated variants with a JmjC domain. ΔJmjC and TPR do not exceed assay background levels (zero), while WT, ΔIDR, ΔTPR and JmjC are all above background. I. Activity of T726K is dependent on post-expression time. WT activity does not change significantly between 24 h (black) to 48 h (grey), whereas in T726K activity is slightly lower than WT after 24 h (blue) and strongly reduced after 48 h (cyan) when comparing c50-values.