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Abstract Objective Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA‐binding protein 43 kDa (TDP‐43) pathology, in addition to accumulations of tau and alpha‐synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. Methods Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole‐exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. Results The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS‐FTLD pattern associated with prominent neuronal and oligodendroglial TDP‐43 pathology, and an atypical limbic 4‐repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). Interpretation OPTN mutations can be associated with extensive TDP‐43 pathology and limbic‐predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS‐FTD spectrum within the same family.

Background Children with chronic illness perform poorer at school, and school well-being (SWB) may mediate this association. We investigated the association between chronic illness and three domains of SWB in children in first grade. Methods Data from a German population-based prospective cohort study were used. Children with chronic illness were identified via their preschool health examination and follow-up parent surveys during first grade. Children were grouped as either (i) having current special health care needs (SHCN), (ii) having at least one physician diagnosis of a chronic illness but no current SHCN, or (iii) being healthy. SWB was assessed at the end of first grade and measured by the Questionnaire for the Assessment of Emotional and Social School Experiences of First and Second Grade Primary School Children. Based on SWB theory and previous frameworks, the following subscales were used: School-Related Self-Concept, Social Integration, and Joy of Learning. The sum score for each subscale was converted into area-transformed T-values (mean 50 and standard deviation 10). Associations between chronic illness groups and SWB subscales were investigated by multivariable linear regression models. Effect estimates were adjusted for potential confounding variables and standardized mean differences (SMD) were calculated. Results Of the 1,490 children included, 15% had current SHCN and 37% had a physician diagnosis of a chronic illness but no current SHCN. Compared to healthy children, children with SHCN had lower scores for the School-Related Self-Concept and the Joy of Learning subscale (SMD −0.18 for both) but not for the Social Integration subscale. In contrast, children with a chronic condition but no SHCN had lower scores only for the Social Integration subscale (SMD −0.12). Conclusions Primary school students with a chronic illness with or without SHCN have lower SWB in some domains compared to their healthy peers. SWB may be a mediator in the association between chronic illness and poor school performance.

Background: Trait mindfulness—the tendency to attend to present-moment experiences without judgment—is negatively correlated with adolescent anxiety and depression. Understanding the neural mechanisms that underlie trait mindfulness may inform the neural basis of psychiatric disorders. However, few studies have identified brain connectivity states that are correlated with trait mindfulness in adolescence, and they have not assessed the reliability of such states. Methods: To address this gap in knowledge, we rigorously assessed the reliability of brain states across 2 functional magnetic resonance imaging scans from 106 adolescents ages 12 to 15 (50% female). We performed both static and dynamic functional connectivity analyses and evaluated the test-retest reliability of how much time adolescents spent in each state. For the reliable states, we assessed associations with self-reported trait mindfulness. Results: Higher trait mindfulness correlated with lower anxiety and depression symptoms. Static functional connectivity (intraclass correlation coefficients 0.31–0.53) was unrelated to trait mindfulness. Among the dynamic brains states that we identified, most were unreliable within individuals across scans. However, one state, a hyperconnected state of elevated positive connectivity between networks, showed good reliability (intraclass correlation coefficient = 0.65). We found that the amount of time that adolescents spent in this hyperconnected state positively correlated with trait mindfulness. Conclusions: By applying dynamic functional connectivity analysis on over 100 resting-state functional magnetic resonance imaging scans, we identified a highly reliable brain state that correlated with trait mindfulness. This brain state may reflect a state of mindfulness, or awareness and arousal more generally, which may be more pronounced in people who are higher in trait mindfulness.

Objective: Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is unknown how the retinal proteome changes as RP disease progresses, and which changes can be prevented, halted, or reversed by gene therapy. Methods: Here, we used a Pde6b-deficient RP gene therapy mouse model and performed untargeted proteomic analysis to identify changes in protein expression during degeneration and after treatment. Results: We demonstrated that Pde6b gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors. Conclusion: In conclusion, the metabolic demands of the retina differ in our Pde6b-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.

Abstract Background Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies. Methods A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions

Abstract Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.

The implementation of automation has already had a considerable impact on chemical and pharmaceutical industrial laboratories. However, academic laboratories have often been more reluctant to adopt such technology due to the high cost of commercial liquid handling systems, although, in many instances, there would be a huge potential to automate repetitive tasks, resulting in elevated productivity. We present here a detailed description of the setup, validation, and utilization of a multifunctional liquid automation (MULA) system that can be used to automate various chemical and biological tasks. Considering that such a setup must be highly customizable, we also designed MULA with respect to modularity, providing detailed insight as far as possible. Including all 3D-printed parts and the used Hamilton gastight micro syringe, the total construction cost is approximately 700 €. This allows us to achieve a highly reliable and accurate system that exceeds the precision of a classical air displacement pipette while still retaining the ability to use closed vial (septa) setups. To encourage other groups to adopt this setup, detailed instructions and tips for every step of the process are provided, along with the complete CAD design of MULA and control code, which are freely available for download under the CC BY NC 3.0 license.

Toxoplasma gondii and Neospora caninum are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) – and several members of this class have proven to be safe and highly active in vitro and in vivo. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited in vitro IC50 values of 120 nM for T. gondii and 480 nM for N. caninum β-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 μM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 μM BKI-1708 in vitro induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (Danio rerio) embryo development during the first 96 h following egg hatching at concentrations up to 2 μM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 μM. In vivo efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9–13 of pregnancy in mice experimentally infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.

Schistosomiasis caused by Schistosoma spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against Plasmodium falciparum, motivating further investigation into their efficacy against Schistosoma mansoni, due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult Schistosoma mansoni yielded 11 candidates with low EC50 values for newly transformed schistosomula (1.12–4.63 μM) and adults (2.78–9.47 μM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of Schistosoma mansoni. The two compounds 2,2′-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride (1) and 2,2′-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride (19), were selected for an in vivo study in Schistosoma mansoni-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction

Abstract The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.

BackgroundIn the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19.MethodsData from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT patients diagnosed with COVID-19 between 1 February 2020 and 31 January 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m2), divided into:

Procrastination, the irrational delay of tasks, is a common occurrence in online learning. Potential negative consequences include a higher risk of drop-outs, increased stress, and reduced mood. Due to the rise of learning management systems (LMS) and learning analytics (LA), indicators of such behavior can be detected, enabling predictions of future procrastination and other dilatory behavior. However, research focusing on such predictions is scarce. Moreover, studies involving different types of predictors and comparisons between the predictive performance of various methods are virtually nonexistent. In this article, we aim to fill these research gaps by analyzing the performance of multiple machine learning algorithms when predicting the delayed or timely submission of online assignments in a higher education setting with two categories of predictors: 1) subjective, questionnaire-based variables and 2) objective, log-data-based indicators extracted from a learning management system. The results show that models with objective predictors consistently outperform models with subjective predictors, and a combination of both variable types performs slightly better with an accuracy of 70%. For each of these three options, a different approach prevailed (gradient boosting machines for the subjective, Bayesian multilevel models for the objective, and Random Forest for the combined predictors). We conclude that careful attention should be paid to the selection of predictors and algorithms before implementing such models in learning management systems.

Young children from low-SES backgrounds are at higher risk for delayed language development, likely due to differences in their home language environment and decreased opportunities for back and forth communicative exchange. Intervention strategies that encourage reciprocal caregiver-child interactions may effectively promote young children's language development and enhance optimal language outcomes. The Filming Interactions to Nurture Development (FIND) program is a brief strength-based video-coaching intervention designed to promote increased back and forth ("serve and return") interactions between caregivers and their children. The current study used data from a randomized controlled trial (RCT) to examine the effectiveness of the FIND program in improving auditory comprehension and expressive communication skills among children from low-SES backgrounds. The current study used a pretest-posttest design to evaluate intervention effects from an RCT with 91 low-SES families. Families with children aged 4 to 36 months old (41.8% female) were randomly assigned to an active control or FIND intervention group. Children's auditory comprehension and expressive communication were assessed using the Preschool Language Scales, Fifth Edition (PLS-5) during both pre- and post-intervention sessions. Children in the FIND intervention group showed significantly increased expressive communication skills and a non-significant increase in auditory comprehension skills across the intervention period. In contrast, children in the active control group showed non-significant changes in expressive communication and a statistically significant decline in auditory comprehension abilities between pre- and post-intervention assessments. All analyses controlled for sex, age, and home language. This study provides preliminary evidence that the FIND intervention promotes the development of expressive and receptive language skills among young children in high-stress, low-SES environments.

Studies on mentored learning to teach commonly focus on the quality of formally arranged mentoring relationships, leaving aside the informal sources of support that surround the mentor-mentee dyad. In this exploratory study, we broaden the scope and investigate how two distinct formal mentoring approaches interact with the informal support provided at teacher training schools in shaping the professional development of beginning teachers. Self-reports from 583 German beginning teachers on mentoring support, peer support, and collegial support are used to identify typical patterns of support during teacher induction. By means of latent class analysis, five support classes with qualitative differences are identified and subsequently compared with regard to their professional skills, self-efficacy, and emotional exhaustion using the BCH 3-step approach. Findings indicate significant differences across groups and a complementary relation between formal and informal support. Implications for effective teacher support within future teacher education are discussed.