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Secondary electron cascades were measured in high purity single-crystalline chemical vapor deposition (CVD) diamond, following exposure to ultrashort hard x-ray pulses (140 fs full width at half maximum, 8.9 keV energy) from the Sub-Picosecond Pulse Source at the Stanford Linear Accelerator Center. We report measurements of the pair creation energy and of drift mobility of carriers in two CVD diamond crystals. This was done for the first time using femtosecond x-ray excitation. Values for the average pair creation energy were found to be 12.17±0.57 and 11.81±0.59 eV for the two crystals, respectively. These values are in good agreement with recent theoretical predictions. The average drift mobility of carriers, obtained by the best fit to device simulations, was μh=2750 cm2/V s for holes and was μe=2760 cm2/V s for electrons. These mobility values represent lower bounds for charge mobilities due to possible polarization of the samples. The results demonstrate outstanding electric properties and the enormous potential of diamond in ultrafast x-ray detectors. [ABSTRACT FROM AUTHOR]

This article presents a study report of the fungistatic effects of the root microflora of grey alder and Norway spruce with Fomes annosus as test fungus. The study was conducted at the Department of Forest Mycology and Pathology, Swedish University of Agricultural Science in Uppsala, Sweden. This comparative study reveals that the significantly higher frequency of actinomycetes in the alder rhizosphere probably constituted the main difference in this respect. The importance of fungi seemed to be about equal in the rhizosphere of the two tree species. Methods for studies of antagonism are tested and discussed in this article.

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism., Competing Interests: BW, ML, EM, PC, VE, CB, CA, SS, EM, PK, JR, HR, JL, RJ No competing interests declared, (© 2023, Wadsworth et al.)

We report the findings of a multi-language and multi-lab investigation of young infants' ability to discriminate lexical tones as a function of their native language, age and language experience, as well as of tone properties. Given the high prevalence of lexical tones across human languages, understanding lexical tone acquisition is fundamental for comprehensive theories of language learning. While there are some similarities between the developmental course of lexical tone perception and that of vowels and consonants, findings for lexical tones tend to vary greatly across different laboratories. To reconcile these differences and to assess the developmental trajectory of native and non-native perception of tone contrasts, this study employed a single experimental paradigm with the same two pairs of Cantonese tone contrasts (perceptually similar vs. distinct) across 13 laboratories in Asia-Pacific, Europe and North-America testing 5-, 10- and 17-month-old monolingual (tone, pitch-accent, non-tone) and bilingual (tone/non-tone, non-tone/non-tone) infants. Across the age range and language backgrounds, infants who were not exposed to Cantonese showed robust discrimination of the two non-native lexical tone contrasts. Contrary to this overall finding, the statistical model assessing native discrimination by Cantonese-learning infants failed to yield significant effects. These findings indicate that lexical tone sensitivity is maintained from 5 to 17 months in infants acquiring tone and non-tone languages, challenging the generalisability of the existing theoretical accounts of perceptual narrowing in the first months of life. RESEARCH HIGHLIGHTS: This is a multi-language and multi-lab investigation of young infants' ability to discriminate lexical tones. This study included data from 13 laboratories testing 5-, 10-, and 17-month-old monolingual (tone, pitch-accent, non-tone) and bilingual (tone/non-tone, non-tone/non-tone) infants. Overall, infants discriminated a perceptually similar and a distinct non-native tone contrast, although there was no evidence of a native tone-language advantage in discrimination. These results demonstrate maintenance of tone discrimination throughout development., (© 2023 John Wiley & Sons Ltd.)

Language is a universal human ability, acquired readily by young children, who otherwise struggle with many basics of survival. And yet, language ability is variable across individuals. Naturalistic and experimental observations suggest that children's linguistic skills vary with factors like socioeconomic status and children's gender. But which factors really influence children's day-to-day language use? Here, we leverage speech technology in a big-data approach to report on a unique cross-cultural and diverse data set: >2,500 d-long, child-centered audio-recordings of 1,001 2- to 48-mo-olds from 12 countries spanning six continents across urban, farmer-forager, and subsistence-farming contexts. As expected, age and language-relevant clinical risks and diagnoses predicted how much speech (and speech-like vocalization) children produced. Critically, so too did adult talk in children's environments: Children who heard more talk from adults produced more speech. In contrast to previous conclusions based on more limited sampling methods and a different set of language proxies, socioeconomic status (operationalized as maternal education) was not significantly associated with children's productions over the first 4 y of life, and neither were gender or multilingualism. These findings from large-scale naturalistic data advance our understanding of which factors are robust predictors of variability in the speech behaviors of young learners in a wide range of everyday contexts., Competing Interests: Competing interests statement:The authors declare no competing interest.

Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate transcription factor (TF)-DNA affinities and apparent on-rates by about 70-fold by directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density, with impacts well predicted by statistical mechanics. Confirming that STRs also affect TF binding in cells, neural networks trained only on in vivo occupancies predicted effects identical to those observed in vitro. Approximately 90% of TFs preferentially bound STRs that need not resemble known motifs, providing a cis -regulatory mechanism to target TFs to genomic sites.

Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin β1, only some integrin β7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)

RNAs are central to fundamental biological processes in all known organisms. The set of possible intramolecular interactions of RNA nucleotides defines the range of alternative structural conformations of a specific RNA that can coexist, and these structures enable functional catalytic properties of RNAs and/or their productive intermolecular interactions with other RNAs or proteins. However, the immense combinatorial space of potential RNA sequences has precluded predictive mapping between RNA sequence and molecular structure and function. Recent advances in high-throughput approaches in vitro have enabled quantitative thermodynamic and kinetic measurements of RNA-RNA and RNA-protein interactions, across hundreds of thousands of sequence variations. In this Review, we explore these techniques, how they can be used to understand RNA function and how they might form the foundations of an accurate model to predict the structure and function of an RNA directly from its nucleotide sequence. The experimental techniques and modelling frameworks discussed here are also highly relevant for the sampling of sequence-structure-function space of DNAs and proteins., (© 2023. Springer Nature Limited.)

Advantageous inequity aversion (i.e., the tendency to respond negatively to unfairness that benefits oneself) usually develops in 6-8-year-olds. However, little is known about the selection pressures that might have shaped this phenomenon. Using data collected from 120 4-8-year-old Finnish children, we tested two evolutionary explanations for the development of advantageous inequity aversion: reciprocal altruism (i.e., benefiting from sharing when the roles are likely reversed in the future) and inclusive fitness (i.e., benefiting from sharing with biological relatives that carry the same alleles). We first successfully replicated a previous experiment, showing that 6-8-year-olds display advantageous inequity aversion by preferring to throw away a resource rather than keep it for themselves. Here, this behavior was also displayed in 5-year-olds. Using a novel experiment, we then asked children to distribute five erasers between themselves, a sibling, a peer, and a stranger. That is, an equal distribution was only possible if throwing away one eraser. We found no support for advantageous inequity aversion being shaped by either inclusive fitness or reciprocal altruism. Future studies could investigate costly signaling and adherence to social norms to avoid negative consequences as ultimate explanations for advantageous inequity aversion.

Nitric oxide (NO) is a signaling molecule produced by NO synthases (NOS1-3) to control processes such as neurotransmission, vascular permeability, and immune function. Although myeloid cell-derived NO has been shown to suppress T-cell responses, the role of NO synthesis in T cells themselves is not well understood. Here, we showed that significant amounts of NO were synthesized in human and murine CD8+ T cells following activation. Tumor growth was significantly accelerated in a T cell-specific, Nos2-null mouse model. Genetic deletion of Nos2 expression in murine T cells altered effector differentiation, reduced tumor infiltration, and inhibited recall responses and adoptive cell transfer function. These data show that endogenous NO production plays a critical role in T cell-mediated tumor immunity., (©2022 The Authors; Published by the American Association for Cancer Research.)

Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from patients with severe COVID-19 every third to seventh day during hospitalization and every third month after recovery. We profiled their antigen-specific immune cell dynamics by combining single-cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq), and B cell receptor-Seq (BCR-Seq) with oligo-tagged antigen baits. While the proportion of Spike receptor binding domain-specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen-specific cells, and affinity maturation was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to 1 year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen-specific B cell responses in longitudinally sampled patients infected with COVID-19.

Background: The viral kinetics of SARS-CoV-2 has been considered clinically important. While remdesivir and corticosteroids are recommended for COVID-19 patients requiring oxygen support, there is a limited number of published reports on viral kinetics in hospitalised patients with COVID-19 treated with remdesivir or corticosteroids., Methods: We conducted a retrospective study by collecting longitudinal samples from the nasopharynx/throat of 123 hospitalised patients (median age 55 years, 74% male) with COVID-19, to evaluate the effects of remdesivir and corticosteroid treatment on viral RNA levels. The subjects were divided into four groups: those receiving remdesivir ( n  = 25), betamethasone ( n  = 41), both ( n  = 15), or neither ( n  = 42). Time to viral RNA clearance was analysed using Kaplan-Meier plots, categorical data were analysed using Fisher's exact test, and Kruskal-Wallis for continuous data. Viral RNA decline rate was analysed using a mixed effect model., Results: We found no significant difference in SARS-CoV-2 RNA decline rate or time to SARS-CoV-2 RNA clearance between the groups. Moreover, clinical status at baseline was not correlated with time to viral clearance., Conclusions: Since SARS-CoV-2 RNA kinetics was not affected by treatment, repeated sampling from the upper respiratory tract cannot be used to evaluate treatment response.

Sequence-specific binding of proteins to DNA is essential for accessing genetic information. We derive a model that predicts an anticorrelation between the macroscopic association and dissociation rates of DNA binding proteins. We tested the model for thousands of different lac operator sequences with a protein binding microarray and by observing kinetics for individual lac repressor molecules in single-molecule experiments. We found that sequence specificity is mainly governed by the efficiency with which the protein recognizes different targets. The variation in probability of recognizing different targets is at least 1.7 times as large as the variation in microscopic dissociation rates. Modulating the rate of binding instead of the rate of dissociation effectively reduces the risk of the protein being retained on nontarget sequences while searching.

Background: The risk of SARS-CoV-2 infection among health care workers (HCWs) is a concern, but studies that conclusively determine whether HCWs are over-represented remain limited. Furthermore, methods used to confirm past infection vary and the immunological response after mild COVID-19 is still not well defined., Method: 314 HCWs were recruited from a Swedish Infectious Diseases clinic caring for COVID-19 patients. IgG antibodies were measured using two commercial assays (Abbot Architect nucleocapsid (N)-assay and YHLO iFlash-1800 N and spike (S)-assays) at five time-points, from March 2020 to January 2021, covering two pandemic waves. Seroprevalence was assessed in matched blood donors at three time-points. More extensive analyses were performed in 190 HCWs in September/October 2020, including two additional IgG-assays (DiaSorin LiaisonXL S1/S2 and Abbot Architect receptor-binding domain (RBD)-assays), neutralizing antibodies (NAbs), and CD4 + T-cell reactivity using an in-house developed in vitro whole-blood assay based on flow cytometric detection of activated cells after stimulation with Spike S1-subunit or Spike, Membrane and Nucleocapsid (SMN) overlapping peptide pools., Findings: Seroprevalence was higher among HCWs compared to sex and age-matched blood donors at all time-points. Seropositivity increased from 6.4% to 16.3% among HCWs between May 2020 and January 2021, compared to 3.6% to 11.9% among blood donors. We found significant correlations and high levels of agreement between NAbs and all four commercial IgG-assays. At 200-300 days post PCR-verified infection, there was a wide variation in sensitivity between the commercial IgG-assays, ranging from <30% in the N-assay to >90% in the RBD-assay. There was only moderate agreement between NAbs and CD4 + T-cell reactivity to S1 or SMN. Pre-existing CD4 + T-cell reactivity was present in similar proportions among HCW who subsequently became infected and those that did not., Conclusions: HCWs in COVID-19 patient care in Sweden have been infected with SARS-CoV-2 at a higher rate compared to blood donors. We demonstrate substantial variation between different IgG-assays and propose that multiple serological targets should be used to verify past infection. Our data suggest that CD4 + T-cell reactivity is not a suitable measure of past infection and does not reliably indicate protection from infection in naive individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marklund, Leach, Nyström, Lundgren, Liljeqvist, Nilsson, Yilmaz, Andersson, Bemark and Gisslén.)

When speaking to infants, parents typically use infant-directed speech, a speech register that in several aspects differs from that directed to adults. Vowel hyperarticulation, that is, extreme articulation of vowels, is one characteristic sometimes found in infant-directed speech, and it has been suggested that there exists a relationship between how much vowel hyperarticulation parents use when speaking to their infant and infant language development. In this study, the relationship between parent vowel hyperarticulation and phonetic complexity of infant vocalizations is investigated. Previous research has shown that on the level of subject means, a positive correlational relationship exists. However, the previous findings do not provide information about the directionality of that relationship. In this study the relationship is investigated on a conversational turn level, which makes it possible to draw conclusions on whether the behavior of the infant is impacting the parent, the behavior of the parent is impacting the infant, or both. Parent vowel hyperarticulation was quantified using the vhh-index, a measure that allows vowel hyperarticulation to be estimated for individual vowel tokens. Phonetic complexity of infant vocalizations was calculated using the Word Complexity Measure for Swedish. Findings were unexpected in that a negative relationship was found between parent vowel hyperarticulation and phonetic complexity of the immediately following infant vocalization. Directionality was suggested by the fact that no such relationship was found between infant phonetic complexity and vowel hyperarticulation of the immediately following parent utterance. A potential explanation for these results is that high degrees of vowel hyperarticulation either provide, or co-occur with, large amounts of phonetic and/or linguistic information, which may occupy processing resources to an extent that affects production of the next vocalization., (Copyright © 2021 Marklund, Marklund and Gustavsson.)