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Abstract The documentation and understanding of variations in the Earth's magnetic field through time is fundamental for several disciplines, but current geomagnetic models rely on datasets heavily biased toward the mid‐ and high northern latitudes. The African continent and surrounding islands and oceans are particularly underrepresented. Here, we present a new record of paleo‐secular variation (PSV) of the inclinations over the last 23 ka from Lake Chala, situated at 3°S near Mt Kilimanjaro in eastern equatorial Africa. This groundwater‐fed crater lake is characterized by a high sedimentation rate (ca. 1 cm/10 years) and a particularly well‐constrained age model based on 210Pb and 14C dating. The magnetic mineralogy of the sediments is tested with rock magnetic analyses. The Lake Chala inclination record shows four highs and lows over 20 ka and compares well with that of Lake Malawi (10°S) between 20 and 16.2 ka, and from 9.8 to 2.6 ka. This record is linked to PSV records at Lakes Victoria and Malawi using a sequence slotting technique to generate a composite PSV model for east Africa. Analyzed at best‐possible resolutions up to 200 years, the Lake Chala PSV record not only represents an important contribution to improve our understanding of local and global features of the Earth's magnetic field. It also expands the utility of paleomagnetism as a key tool for dating and correlation both for archeological sites throughout East Africa and the many volcanoes, active or dormant, of the East African Rift System.

Abstract We report the characterization of anthropogenic magnetic particulate matter (MPM) collected on leaves from roadside Callistemon (bottlebrush) trees from Lahore, Pakistan, and on known sources of traffic‐related particulates to assess the potential of first‐order reversal curve (FORC) diagrams to discriminate between different sources of anthropogenic magnetic particles. Magnetic measurements on leaves indicate the presence of surface‐oxidized magnetite spanning the superparamagnetic (

The combination of the austempered ductile iron mechanical properties strongly depend on the parameters used on the austempering cycle. On this study, the influence of austempering time and austenitizing temperature on the properties of a ductile iron were evaluated. A metallic bath of Zamak at 380°C was used as an austempering mean. A set of ductile iron blocks were austenitized at 900°C for 90 minutes and submitted to different austempering times in order to determine the best combination of microstructural and mechanical properties. After the definition of the time of austempering, the reduction of the austenitizing temperature was evaluated. The best combination of properties was obtained with austenitizing at 860°C and austempering during 60 minutes.

Background: Different types of early-life adversity (ELA) have been associated with children's brain structure and function. However, understanding the disparate influence of distinct adversity exposures on the developing brain remains a major challenge., Methods: This study investigates the neural correlates of 10 robust dimensions of ELA identified through exploratory factor analysis in a large community sample of youth from the Adolescent Brain Cognitive Development Study. Brain age models were trained, validated, and tested separately on T1-weighted (n = 9524), diffusion tensor (n = 8834), and resting-state functional (n = 8233) magnetic resonance imaging data from two time points (mean age = 10.7 years, SD = 1.2, age range = 8.9-13.8 years)., Results: Bayesian multilevel modeling supported distinct associations between different types of ELA exposures and younger- and older-looking brains. Dimensions generally related to emotional neglect, such as lack of primary and secondary caregiver support and lack of caregiver supervision, were associated with lower brain age gaps, i.e., younger-looking brains. In contrast, dimensions generally related to caregiver psychopathology, trauma exposure, family aggression, substance use and separation from biological parent, and socioeconomic disadvantage and neighborhood safety were associated with higher brain age gaps, i.e., older-looking brains., Conclusions: The findings suggest that dimensions of ELA are differentially associated with distinct neurodevelopmental patterns, indicative of dimension-specific delayed and accelerated brain maturation., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Detecting errors and adapting behavior accordingly constitutes an integral aspect of cognition. Previous studies have linked neural correlates of error processing (e.g., error-related negativity (ERN) and error-related positivity (Pe)) to task performance and broader behavioral constructs, but few studies examined how these associations manifest in adolescence. In this study, we examined neural error processing markers and their behavioral associations in an adolescent/emerging adult sample (N = 143, M age = 18.0 years, range 11-25 years), employing a stop-signal task. Linear regressions were conducted using bootstrap resampling to explore associations between ERN/Pe peak amplitudes and latencies, stop accuracy, stop-signal reaction time (SSRT), and post-error slowing, as well as self-reported substance-related risks and problems and externalizing problems. After adjusting for age and sex, smaller frontocentral Pe amplitude and later Pe latency were associated with longer SSRT, and later Pe latency was associated with lower stop accuracy. This might indicate that the Pe, which is thought to reflect conscious error processing, reflects task performance on a response inhibition task better than the ERN, which reflects subconscious error processing. After correcting for multiple testing, there were no associations between ERN/Pe parameters and substance-related or externalizing problems, and no age interactions for these associations were detected., Competing Interests: Declaration of Competing Interest One of the authors (C.K. Tamnes) is an Editorial Board Member for Developmental Cognitive Neuroscience and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Parental mental health is associated with children's emotion regulation (ER) and risk for psychopathology. The relationship between parental psychopathology and children's functional ER networks and whether connectivity patterns mediate the relationship between parent and youth psychopathology remains unexplored. Using resting-state functional magnetic resonance imaging data from the Adolescent Brain Cognitive Development Study (N = 4202, mean age = 10.0) and a multilevel approach, we analyzed the relationship between self-reported parental psychopathology and their offsprings' connectivity of four ER networks, as well as associations with self-reported youth psychopathology at a 3-year follow-up. Parental internalizing and total problems were associated with 1) higher connectivity between a subcortical-cortical integrative and ventrolateral prefrontal cortical (PFC) network, 2) lower connectivity between dorsolateral and ventrolateral PFC networks involved in cognitive aspects of ER, and 3) lower connectivity within a subcortical ER network (β = -0.05-0.04). Parental externalizing and total problems were associated with lower connectivity within the integrative network (β ext = -0.05; β tot = -0.04). Mediation analyses yielded direct effects of parental to youth psychopathology, but no mediation effect of ER network connectivity. Overall, our results show that ER network connectivity in youth is related to parental psychopathology, yet do not explain intergenerational transmission of psychopathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Multiple myeloma (MM) patients are at high risk of severe infections including COVID-19 due to an immune dysregulation affecting both innate and adaptive immune responses. However, our understanding of the immune responses to infection and vaccination in MM patients is limited. To gain more detailed insights into infection- and vaccine-elicited T cell immunity in MM, we studied the CD8+ T cell response on the single-epitope level in SARS-CoV-2 convalescent and mRNA-vaccinated MM patients., Methods: We compared peptide/MHC class I tetramer-enriched SARS-CoV-2-specific CD8+ T cells and antibody responses in MM patients (convalescent: n = 16, fully vaccinated: n = 5, vaccinated convalescent: n = 5) and healthy controls (HCs) (convalescent: n = 58, fully vaccinated: n = 7) either after infection with SARS-CoV-2 alone, complete mRNA vaccination or SARS-CoV-2 infection and single-shot mRNA vaccination (hybrid immunity)., Results: MM patients have lower frequencies and a lower proportion of fully functional virus-specific CD8+ T cells compared to HCs, after both SARS-CoV-2 infection and vaccination. CD8+ T cell memory subset distribution in MM patients is skewed towards reduced frequencies of central memory (T CM ) T cells and higher frequencies of effector memory 1 (T EM1 ) T cells. In contrast, the humoral immune response was comparable in both cohorts after viral clearance. Notably, CD8+ T cell frequencies as well as the humoral immune response were improved by a single dose of mRNA vaccine in convalescent MM patients., Conclusions: MM patients have relative immunological deficiencies in SARS-CoV-2 immunity but benefit from hybrid immunity. These findings underline the relevance of vaccinations in this vulnerable patient group.

Behavioral parameters obtained from cognitive control tasks have been linked to electrophysiological markers. Yet, most previous research has investigated only a few specific behavioral parameters at a time. An integrated approach with simultaneous consideration of multiple aspects of behavior may better elucidate the development and function of cognitive control. Here, we aimed to identify shared patterns between cognitive control behavior and electrophysiological markers using stop-signal task data and EEG recordings from an adolescent sample (n = 193, aged 11-25 years). We extracted behavioral variables covering various aspects of RT, accuracy, inhibition, and decision-making processes, as well as amplitude and latency of the ERPs N1, N2, and P3. To identify shared patterns between the two sets of variables, we employed a principal component analysis and a canonical correlation analysis. First, we replicated previously reported associations between various cognitive control behavioral parameters. Next, results from the canonical correlation analysis showed that overall good task performance was associated with fast and strong neural processing. Furthermore, the canonical correlation was affected by age, indicating that the association varies depending on age. The present study suggests that although distributional and computational methods can be applied to extract specific behavioral parameters, they might not capture specific patterns of cognitive control or electrophysiological brain activity in adolescents., (© 2024 Massachusetts Institute of Technology.)

Several mental disorders emerge during childhood or adolescence and are often characterized by socioemotional difficulties, including alterations in emotion perception. Emotional facial expressions are processed in discrete functional brain modules whose connectivity patterns encode emotion categories, but the involvement of these neural circuits in psychopathology in youth is poorly understood. This study examined the associations between activation and functional connectivity patterns in emotion circuits and psychopathology during development. We used task-based fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC, N = 1221, 8-23 years) and conducted generalized psycho-physiological interaction (gPPI) analyses. Measures of psychopathology were derived from an independent component analysis of questionnaire data. The results showed positive associations between identifying fearful, sad, and angry faces and depressive symptoms, and a negative relationship between sadness recognition and positive psychosis symptoms. We found a positive main effect of depressive symptoms on BOLD activation in regions overlapping with the default mode network, while individuals reporting higher levels of norm-violating behavior exhibited emotion-specific lower functional connectivity within regions of the salience network and between modules that overlapped with the salience and default mode network. Our findings illustrate the relevance of functional connectivity patterns underlying emotion processing for behavioral problems in children and adolescents., (© 2024. The Author(s).)

Emotion recognition (ER) declines with increasing age, yet little is known whether this observation is based on structural brain changes conveyed by differential atrophy. To investigate whether age-related ER decline correlates with reduced grey matter (GM) volume in emotion-related brain regions, we conducted a voxel-based morphometry analysis using data of the Human Connectome Project-Aging (N = 238, aged 36-87) in which facial ER was tested. We expected to find brain regions that show an additive or super-additive age-related change in GM volume indicating atrophic processes that reduce ER in older adults. The data did not support our hypotheses after correction for multiple comparisons. Exploratory analyses with a threshold of P < 0.001 (uncorrected), however, suggested that relationships between GM volume and age-related general ER may be widely distributed across the cortex. Yet, small effect sizes imply that only a small fraction of the decline of ER in older adults can be attributed to local GM volume changes in single voxels or their multivariate patterns., (© The Author(s) 2023. Published by Oxford University Press.)

Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences. We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort. Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD). Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Liver transplant recipients (LTRs) demonstrate a reduced response to COVID-19 mRNA vaccination; however, a detailed understanding of the interplay between humoral and cellular immunity, especially after a third (and fourth) vaccine dose, is lacking., Methods: We longitudinally compared the humoral, as well as CD4+ and CD8+ T-cell, responses between LTRs (n = 24) and healthy controls (n = 19) after three (LTRs: n = 9 to 16; healthy controls: n = 9 to 14 per experiment) to four (LTRs: n = 4; healthy controls: n = 4) vaccine doses, including in-depth phenotypical and functional characterization., Results: Compared to healthy controls, development of high antibody titers required a third vaccine dose in most LTRs, while spike-specific CD8+ T cells with robust recall capacity plateaued after the second vaccine dose, albeit with a reduced frequency and epitope repertoire compared to healthy controls. This overall attenuated vaccine response was linked to a reduced frequency of spike-reactive follicular T helper cells in LTRs., Conclusion: Three doses of a COVID-19 mRNA vaccine induce an overall robust humoral and cellular memory response in most LTRs. Decisions regarding additional booster doses may thus be based on individual vaccine responses as well as evolution of novel variants of concern., Impact and Implications: Due to immunosuppressive medication, liver transplant recipients (LTR) display reduced antibody titers upon COVID-19 mRNA vaccination, but the impact on long-term immune memory is not clear. Herein, we demonstrate that after three vaccine doses, the majority of LTRs not only exhibit substantial antibody titers, but also a robust memory T-cell response. Additional booster vaccine doses may be of special benefit for a small subset of LTRs with inferior vaccine response and may provide superior protection against evolving novel viral variants. These findings will help physicians to guide LTRs regarding the benefit of booster vaccinations., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Early detection and management of acute trauma hemorrhage and coagulopathy have been associated with improved outcomes, but local infrastructure, logistics and clinical strategies may differ., Methods: To assess local differences in infrastructure, logistics and clinical management of acute trauma hemorrhage and coagulopathy we have conducted a web-based survey amongst clinicians working in DGU ® -certified supraregional, regional and local trauma centers., Results: 137/1875 respondents completed the questionnaire yielding a response rate of 7.3%. The majority specified to work as head of department or senior consultant (95%) in trauma/orthopedic surgery (80%) of supraregional (38%), regional (34%) or local (27%) trauma centers. Conventional coagulation assays are most frequently used to monitor bleeding trauma patients. Only half of the respondents (53%) rely on extended coagulation tests, e.g. viscoelastic hemostatic assays. Tests to assess preinjury use of direct oral anticoagulants and platelet inhibitors are still not widely available and vary according to level of care. Conventional blood products are widely available but there remain differences between trauma centers of different level of care to access other hemostatic therapies, e.g. coagulation factor concentrates. Trauma centers of higher level of care are more likely to implement treatment protocols., Conclusion: This survey confirms still existing differences in infrastructure, logistics and clinical practice management for the detection of acute trauma hemorrhage and coagulopathy amongst DGU ® -certified supraregional, regional and local trauma centers. Further work is recommended to locally implement diagnostics, therapies and treatment algorithms compliant to current guidelines to ensure the best possible outcomes in bleeding trauma patients., (© 2021. The Author(s).)

Immunization with two mRNA vaccine doses elicits robust spike-specific CD8 + T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8 + T cell response remains unclear. Here we show that spike-specific CD8 + T cells are activated and expanded in all analyzed individuals receiving the 3 rd and 4 th mRNA vaccine shots. This CD8 + T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8 + T memory stem cell pool is not affected by the 3 rd vaccination. Both 4 th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8 + T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8 + T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern., (© 2022. The Author(s).)

The need for dental rehabilitations under general anesthesia (DRGAs) is continuously increasing, particularly for dental treatment of children. The present retrospective cohort study aimed to investigate potential risk factors for repeated need of DRGA in a cohort of patients from a private pediatric dental practice. Demographic and anamnestic data, dental status, and treatments performed during DRGA were retrospectively analyzed from the electronic dental charts of 1155 children that received at least one DRGA between October 2016 and December 2021. The median age of all children was 5 years at time of their first DRGA. The rate of repeated DRGAs was 9%. Patients with repeated need of DRGA were significantly younger at time of their first DRGA and revealed significantly more often a history of preterm birth and current use of a baby bottle as compared to patients with only one DRGA. There were significantly fewer treatments (regardless of type) in the second DRGA than at the first. Within the limitations of this study, young age at first DRGA, a history of preterm birth, and current use of a baby bottle may be risk factors for repeated need of DRGA. The search for effective strategies to minimize the repeated need for DRGA in children remains critical.

Arsenic is a toxic metalloid that affects human health by causing numerous diseases and by being used in the treatment of acute promyelocytic leukemia. Saccharomyces cerevisiae (budding yeast) has been extensively utilized to elucidate the molecular mechanisms underlying arsenic toxicity and resistance in eukaryotes. In this study, we applied a genomic DNA overexpression strategy to identify yeast genes that provide arsenic resistance in wild-type and arsenic-sensitive S. cerevisiae cells. In addition to known arsenic-related genes, our genetic screen revealed novel genes, including PHO86, VBA3, UGP1, and TUL1, whose overexpression conferred resistance. To gain insights into possible resistance mechanisms, we addressed the contribution of these genes to cell growth, intracellular arsenic, and protein aggregation during arsenate exposure. Overexpression of PHO86 resulted in higher cellular arsenic levels but no additional effect on protein aggregation, indicating that these cells efficiently protect their intracellular environment. VBA3 overexpression caused resistance despite higher intracellular arsenic and protein aggregation levels. Overexpression of UGP1 led to lower intracellular arsenic and protein aggregation levels while TUL1 overexpression had no impact on intracellular arsenic or protein aggregation levels. Thus, the identified genes appear to confer arsenic resistance through distinct mechanisms but the molecular details remain to be elucidated., (© 2022 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8 + T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines., (© 2022. The Author(s).)

Conventional approaches to isolate and characterize nanobodies are laborious. We combine phage display, multivariate enrichment, next-generation sequencing, and a streamlined screening strategy to identify numerous anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nanobodies. We characterize their potency and specificity using neutralization assays and hydrogen/deuterium exchange mass spectrometry (HDX-MS). The most potent nanobodies bind to the receptor binding motif of the receptor binding domain (RBD), and we identify two exceptionally potent members of this category (with monomeric half-maximal inhibitory concentrations around 13 and 16 ng/ml). Other nanobodies bind to a more conserved epitope on the side of the RBD and are able to potently neutralize the SARS-CoV-2 founder virus (42 ng/ml), the Beta variant (B.1.351/501Y.V2) (35 ng/ml), and also cross-neutralize the more distantly related SARS-CoV-1 (0.46 μg/ml). The approach presented here is well suited for the screening of phage libraries to identify functional nanobodies for various biomedical and biochemical applications.

Importance: Tranexamic acid is widely available and used off-label in patients with bleeding traumatic injury, although the literature does not consistently agree on its efficacy and safety., Objective: To examine the association of tranexamic acid administration with mortality and thromboembolic events compared with no treatment or with placebo in patients with traumatic injury in the literature., Data Sources: On March 23, 2021, PubMed, Embase, and the Cochrane Library were searched for eligible studies published between 1986 and 2021., Study Selection: Randomized clinical trials and observational studies investigating tranexamic acid administration compared with no treatment or placebo among patients with traumatic injury and traumatic brain injury who were 15 years or older were included. Included studies were published in English or German. The electronic search yielded 1546 records, of which 71 were considered for full-text screening. The selection process was performed independently by 2 reviewers., Data Extraction and Synthesis: The study followed the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 2 independent reviewers and pooled using the inverse-variance random-effects model., Main Outcomes and Measures: Outcomes were formulated before data collection and included mortality at 24 hours and 28 and 30 days (1 month) as well as the incidence of thromboembolic events and the amount of blood products administered. Owing to missing data, overall mortality was added and the amount of blood products administered was discarded., Results: Thirty-one studies with a total of 43 473 patients were included in the systematic review. The meta-analysis demonstrated that administration of tranexamic acid was associated with a significant decrease in 1-month mortality compared with the control cohort (risk ratio, 0.83 [95% CI, 0.71-0.97]; I2 = 35%). The results of meta-analyses for 24-hour and overall mortality and thromboembolic events were heterogeneous and could not be pooled. Further investigations on clinical heterogeneity showed that populations with trauma and trial conditions differed markedly., Conclusions and Relevance: These findings suggest that tranexamic acid may be beneficial in various patient populations with trauma. However, reasonable concerns about potential thromboembolic events with tranexamic acid remain.

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer-dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants., (© 2022. The Author(s).)

The approval of the first digital health applications (DiGA) in October 2020 resulted in a lot of buzz - not only in the healthcare sector but also beyond. The integration of DiGA to the public healthcare system was seen as a significant innovation and stakeholders worldwide were looking to Germany. How did the start of the DiGA innovation project go and what is the current standing? The first months of DiGA becoming part of standard care brought new experiences and knowledge to manufacturers, doctors and patients as well as to health insurance companies and associations. More than six months later, it is time for a preliminary review.This article looks at the achievements so far as well as the status quo of DiGA in the market as of March 2021. It also focuses on current and upcoming challenges that the various stakeholders face on the way to integrate DiGA into standard care in a widespread and sustainable way., (© 2021. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified Saccharomyces cerevisiae deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. This article has an associated First Person interview with the first authors of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Multivalent antibody constructs have a broad range of clinical and biotechnological applications. Nanobodies are especially useful as components for multivalent constructs as they allow increased valency while maintaining a small molecule size. We here describe a novel, rapid method for the generation of bi- and multivalent nanobody constructs with oriented assembly by Cu-free strain promoted azide-alkyne click chemistry (SPAAC). We used sortase A for ligation of click chemistry functional groups site-specifically to the C-terminus of nanobodies before creating C-to-C-terminal nanobody fusions and 4-arm polyethylene glycol (PEG) tetrameric nanobody constructs. We demonstrated the viability of this approach by generating constructs with the SARS-CoV-2 neutralizing nanobody Ty1. We compared the ability of the different constructs to neutralize SARS-CoV-2 pseudotyped virus and infectious virus in neutralization assays. The generated dimers neutralized the virus similarly to a nanobody-Fc fusion variant, while a 4-arm PEG based tetrameric Ty1 construct dramatically enhanced neutralization of SARS-CoV-2, with an IC 50 in the low picomolar range.

New ways of predicting sperm quality and output performance in young artificial insemination (AI) boars are important for breeding companies to ensure that the pubertal boars delivered to the AI studs have a high chance of meeting minimum quality standards to be used for insemination and therewith dissemination of desirable characteristics. The aim of the current study was to characterize the testicular development of 218 pubertal Piétrain boars (Line 408, Pig Improvement Company) to identify traits with predictable characteristics relative to their sperm quality as an adult AI boar. Scrotum, testes and epididymis were examined ultrasonographically at day (d) 100 (on-test) and 170 (off-test) followed by a computer-assisted grayscale analysis (GSA). Over the test period, paired testicular volume increased 7.3-fold from 22.7 ± 10.8 cm 3 to 166.6 ± 62.2 cm 3 . The right testis was significantly (P = 0.014) larger than the left one at the off-test. Based on the sperm quality (ejaculate volume, sperm concentration, total sperm number, morphologically abnormal sperm and total sperm motility at day 3 of semen storage), 82.11% (n = 179) of the boars were classified as "productive" boars. These boars had a significantly (P = 0.039) larger paired testicular volume than "non-productive" boars (45.9 ± 19.9 cm 3 vs. 38.5 ± 12.6 cm 3 ) at the on-test. For the right testis at on-test, significant differences for the standard deviation of mean gray value (P = 0.022), area under the curve (P = 0.004) and mean gradient value (GRAD, P = 0.030) regarding the future sperm production capacity (SPC) were shown. At off-test, there was a significant difference for minimum gray value (MIN GV, P = 0.003) and mean gray value (P = 0.001) related to SPC. To find SPC related cut-off values for GSA data, a two segmental non-linear regression analysis was carried out indicating breakpoints for GRAD ≥12 and MIN GV ≥ 40 for boars with low SPC. Off-test boars with MIN GV ≥ 40 showed a 2.4 higher risk to display low SPC (Odds ratio = 2.4 [1.1, 5.4]; P = 0.024). The results may enable breeding companies to include new sperm quality associated traits in their boar testing and selection programs., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Several domestic and wildlife species have been shown to possess antibacterial defenses in their ejaculate most probably in order to increase the fertilization success and protect against sexually transmitted pathogens. However, very little is known about the consequences and factors influencing the differences within and between species as far as ejaculate-associated immunity. In the present study, we have analyzed bacterial killing activity (BKA) against Escherichia (E.) coli and Staphylococcus (S.) aureus as well as lysozyme concentrations (LC) in seminal plasma from 60 Fleckvieh bulls. Further, sperm quality and its association with BKA and LC were determined. Twenty percent of the individuals displayed BKA against both bacteria, 78.3% against S. aureus only and 1.7% of the bulls did not indicate any BKA in seminal plasma. No bulls with seminal plasma BKA only against E. coli were identified; implying that 80.0% of the tested bulls had no ejaculate associated defense mechanisms against this gram-negative bacterial species in place. This is in striking contrast to results of Pietrain boars within our previous study, in which 42.8% of the 119 boars expressed an antibacterial activity against E. coli in seminal plasma, 10.9% amongst them with BKA against E. coli only. LC was higher in the bull group with BKA against both bacteria (1.2 ± 0.6 μg/mL) compared to the group with BKA against S. aureus only (0.7 ± 0.3 μg/mL), but - if calculated over all individuals - LC in bulls (0.8 ± 0.4 μg/mL) was lower compared to boars (2.4 ± 1.2 μg/mL). LC showed positive correlations to the age of the bulls and sperm quality as well as a negative relation to bacterial load in raw semen although the highest bacterial contamination was found in animals with seminal plasma BKA against both strains. We discuss the obtained results with regards to possible differences within the microbiome of female and male genital tracts and the reproductive strategies (vaginal vs. uterine depositors) in these two livestock species. Besides identifying the responsible molecules, future phylogenetically controlled comparative studies are needed for a better understanding of the evolution of species differences in ejaculate-associated antibacterial defenses., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of the workshop was to work out concrete plans and steps for implementing patient education courses in an outpatient setting by the collaborative arthritis centers in Germany. Primarily the patient education model of Lower Saxony was illustrated as an example of successful implementation of patient education programs in practice. In this state patient education courses are run in cooperation between the Arthritis Center of Hannover and the League against Rheumatism in Lower Saxony. Both institutions are in discussion with the health insurance companies for paying the costs for the patient education courses. Then the group discussed several important aspects which have to be considered when establishing patient education courses such as recruiting and motivating the trainers, recruiting the participants, choosing adequate rooms, fund raising and responsibilities. The participants considered the patient education model of Lower Saxony as a transferable model for every collaborative arthritis center in Germany and recommended to follow that path.

The article summarizes the state of the art in patient education in rheumatology and describes the goals that have been reached and the problems that have to be solved in the future. Within recent years 6 patient education programs have been developed, 4 additional programs are in progress. Evaluation studies have been conducted for 3 programs showing evidence for the efficacy of patient education in different fields. Furthermore quality standards for patient education in rheumatology have been worked out and train-the-trainer-seminars are held regularly. Most of the activities in patient education take place in inpatient settings because of the lack of financial support for patient education courses in outpatient settings. Therefore future efforts have to concentrate on negotiations with health insurance companies to obtain money for running comprehensive outpatient education courses overall in Germany.