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Abstract Objective The aims of this study were to translate the SAPE questionnaire (Scales of the Attitudes toward People with Epilepsy) questionnaire developed in Germany that assesses attitudes toward people with epilepsy (PWE) into Japanese and to examine its reliability and validity. Methods We crafted the Japanese version of SAPE (SAPE‐J) by drawing upon the original German version. On May 22nd and 23rd, 2023, we surveyed the general public registered with an online research survey service (Cross Marketing Group Inc., Tokyo, Japan) using an online questionnaire. Inclusion criteria were an age of ≥18 years, sufficient reading and speaking skills in Japanese, and the ability to comprehend the Japanese questionnaires. In addition to the translated SAPE‐J, we asked about knowledge of epilepsy, personal experience with epilepsy, and gathered information about age, gender, employment status, education level, marital status, and household income in accordance with the validation of the German version of the SAPE. Results 400 adults from the general public who had heard or read about epilepsy were asked to participate, granted informed consent, and completed the study questionnaire. The SAPE‐J questionnaire has 6 scales: 1. Social Distance; 2. Stereotypes; 3. Concerns when encountering a person with epilepsy (PWE) and emotional reactions differentiated by 4.1 Fear, 4.2. Anger, and 4.3 Pity; with a total of 26 items. The reliability of these scales ranged between acceptable to high (Cronbach's alpha 0.74–0.92) and confirmatory factor analyses (CFA) confirmed the presumed six‐factor structure of the SAPE (factorial validity). Multivariate generalized linear models (GLM) were used to investigate the construct validity and showed that, depending on subscale, different variables such as age, gender, education level, personal contact to PWE, and epilepsy specific knowledge were significant predictors of attitudes. Significance The Japanese version of the SAPE proved reliable and valid for assessing attitudes toward PWE in the Japanese public. Increasing understanding about how to deal with and accept persons with epilepsy may help reduce negative attitudes and fears about the condition. Plain Language Summary The study translated the German SAPE questionnaire, which measures attitudes toward people with epilepsy (PWE), into Japanese and tested its reliability and validity. The Japanese version (SAPE‐J) was created and surveyed online among 400 adults in Japan. The SAPE‐J has 6 scales covering social distance, stereotypes, and emotional reactions like fear, anger, and pity. Reliability was high (Cronbach's alpha 0.74–0.92), and factor analyses confirmed its structure. The study found age, gender, education, and personal contact with PWE influenced attitudes. The SAPE‐J is reliable and valid for assessing attitudes toward PWE in Japan, potentially reducing negative views and fears about epilepsy.

Abstract One of the main unit operations in metallurgical processing plant designs is gold leaching. The traditional cyanidation process was chosen and is currently in widespread use. However, the mining sector is looking for lixiviants other than cyanide. Cyanide’s effects on the environment have made it difficult for humans and other biotic creatures to survive. There is now research to discover a substitute for this cyanide. It is currently argued that thiosulfate is a preferable substitute for cyanide. The effectiveness of thiosulfate as a leaching agent in carbonaceous gold-bearing ores in Ethiopia is discussed in this paper compared to cyanide. The study has looked into the advantages of employing thiosulfate over cyanide from a technical, and economic standpoint. The leaching effects of both lixiviants on carbonaceous gold-bearing ores extracted from MIDROC Legadembi Open Pit mine in Southern Ethiopia, Oromia region, were examined in a laboratory experiment. After 48 h of leaching, it was discovered that thiosulfate has a better and quicker recovery of 91.54% over 61.70% of cyanide recovery. Tables and graphs are used to demonstrate thiosulfate’s technical advantage over cyanide. As a result, this paper provides evidence regarding the Legadembi gold mine in Ethiopia’s amenability to thiosulfate leaching on carbonaceous gold-bearing ores. A further research perspective is also sought for thiosulfate leaching in other refractory ores.

Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

Abstract Background Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. Methods This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10–20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. Discussion This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. Trial registration Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).

Annually, Sierra Leone records an estimated 301 human fatalities due to rabies. Canine vaccination is crucial for rabies prevention and control efforts. However, considerable variability exists in vaccination rates. Reasons for this variation remain unclear. We conducted a cross-sectional study across 2,558 dog-owning households (HHs) to provide insights into factors influencing canine vaccination for targeted prevention and control towards elimination by 2030. First, we described dog ownership practices, then built a probabilistic model to understand factors associated with dog vaccination, and finally used a spatial scan statistic to identify spatial clusters where vaccination rates were low. Our results indicated that only 14% (358/2,558) of participating HHs had fully vaccinated their dogs against rabies. The probability of dog vaccination increased when comparing civil servants to private workers/artisans, with an Odds Ratio(OR) of 1.14 (95% credible interval (Crl) of 0.82-1.56), residing in locations with a veterinary establishment vs. none (OR = 6.43, 95% Crl (4.97-8.35), providing care to dogs vs. allowing dogs to roam freely (OR = 2.38, 95% Crl(1.80-3.17) and owning a single dog vs multiple dogs (OR = 1.20, 95 Crl (0.92-1.56). Conversely, there was a decrease in the estimated probability of vaccination when comparing dog owners located in rural vs. urban areas (OR = 0.58, CrI 95% (0.43-0.78). Latent understanding, a measure of overall understanding of rabies virus, which we estimated using participant education levels and responses to questions about rabies epidemiology, was also an important predictor of vaccination probability (OR = 1.44, 95% Crl (1.04-2.07). The spatial analysis identified high-risk clusters for low vaccination in the cities of Moyamba, with a radius of 40 km, a relative risk (RR) of 1.10, and Bo, with a radius of 19.9 km with RR of 1.11. These data do not support Sierra Leone reaching the 2030 goal of human rabies elimination caused by dogs. Our study highlights a critical need for public outreach and education, improved vaccination rates, increased accessibility to veterinary services, and targeted interventions in Bo and Moyamba to support rabies prevention and control efforts.

Genetically encoded calcium indicators (GECIs) such as GCaMP are invaluable tools in neuroscience to monitor neuronal activity using optical imaging. The viral transduction of GECIs is commonly used to target expression to specific brain regions, can be conveniently used with any mouse strain of interest without the need for prior crossing with a GECI mouse line, and avoids potential hazards due to the chronic expression of GECIs during development. A key requirement for monitoring neuronal activity with an indicator is that the indicator itself minimally affects activity. Here, using common adeno-associated viral (AAV) transduction procedures, we describe spatially confined aberrant Ca2+ microwaves slowly travelling through the hippocampus following expression of GCaMP6, GCaMP7, or R-CaMP1.07 driven by the synapsin promoter with AAV-dependent gene transfer in a titre-dependent fashion. Ca2+ microwaves developed in hippocampal CA1 and CA3, but not dentate gyrus nor neocortex, were typically first observed at 4 wk after viral transduction, and persisted up to at least 8 wk. The phenomenon was robust and observed across laboratories with various experimenters and setups. Our results indicate that aberrant hippocampal Ca2+ microwaves depend on the promoter and viral titre of the GECI, density of expression, as well as the targeted brain region. We used an alternative viral transduction method of GCaMP which avoids this artefact. The results show that commonly used Ca2+-indicator AAV transduction procedures can produce artefactual Ca2+ responses. Our aim is to raise awareness in the field of these artefactual transduction-induced Ca2+ microwaves, and we provide a potential solution.

Rabies perpetuates in Nigeria despite initiatives like the Regional Disease Surveillance System Enhancement Project, with evidence indicating suboptimal canine vaccination rates as a contributing factor. To inform effective planning of mass dog vaccination campaigns, it is crucial to understand the factors associated with variation in canine vaccination rates. We conducted a cross-sectional study in 2022 to understand factors associated with canine vaccination. We used stratified random sampling of the streets and dog-owning households to survey 4162 households from three states and the Federal Capital Territory (FCT). We then built a joint probabilistic model to understand factors associated with dog vaccination and non-vaccination. First, we modelled rabies knowledge as a latent variable indirectly measured with several targeted survey questions. This method allowed a respondent's unobserved understanding of rabies to be estimated using their responses to a collection of survey questions that targeted different aspects of rabies epidemiology and took various possible response distributions (i.e., ordinal, categorical, binary). Second, we modelled factors influencing pet owners' decisions to vaccinate their dogs against rabies and barriers to dog vaccination among dog owners whose dogs were not vaccinated against rabies. Posterior distributions revealed that the probability of dog vaccination was positively associated with the owner's latent knowledge of rabies, civil servant service employment, residence in the FCT, ownership of a single dog, providing care to dogs, and a preference for contemporary treatment following a dog bite. Conversely, non-vaccination was positively associated with private employment, residing in Anambra and Enugu states, owning multiple dogs, allowing dogs to search for leftovers, and a preference for traditional treatment after a dog bite. Cost was the primary barrier against vaccination for dog owners in Anambra and Enugu, while mistrust posed a major challenge for those in the FCT. Owners in areas with veterinary establishments cited cost as a barrier, while those without a veterinary establishment cited access as the primary barrier. Our study underscores the need to enhance rabies knowledge, tailor vaccination campaigns to specific demographics, address financial and access barriers, and combat hesitancy to improve rabies vaccination rates in Nigeria.

Abstract Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.

Abstract Background and objectives 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer’s disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD. Methods 49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and β-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). Results In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD − 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F (3,52) = 3.077, p = 0.005). Conclusion While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.

Abstract Anorexia nervosa (AN) is characterized by emaciation, hyperactivity, and amenorrhea. Imaging studies in AN patients have revealed reductions in grey and white matter volume, which correlate with the severity of neuropsychological deficits. However, the cellular basis for the observed brain atrophy is poorly understood. Although distinct hypothalamic centers, including the arcuate nucleus (ARC) are critically involved in regulating feeding behavior, little is known about potential hypothalamic modifications in this disorder. Since glia e.g. astrocytes and microglia influence neuronal circuits, we investigated the glial changes underlying pathophysiology of starvation in the corpus callosum (CC) and hypothalamus. Female mice were given a limited amount of food once a day and had unlimited access to a running wheel until a 20% weight reduction was achieved (acute starvation). This weight reduction was maintained for two weeks to mimic chronic starvation. Immunohistochemistry was used to quantify the density of astrocytes, microglia, oligodendrocytes, and the staining intensity of neuropeptide Y (NPY), a potent orexigenic peptide. Chronic starvation induced a decreased density of OLIG2+ oligodendrocytes, GFAP+ astrocytes, and IBA1+ microglia in the CC. However, the densities of glial cells remained unchanged in the ARC following starvation. Additionally, the staining intensity of NPY increased after both acute and chronic starvation, indicating an increased orexigenic signaling. Chronic starvation induced glial cell changes in the CC in a mouse model of AN suggesting that glia pathophysiology may play a role in the disease.

Abstract Nicolai maps offer an alternative description of supersymmetric theories via nonlinear and nonlocal transformations characterized by the so-called ‘free-action’ and ‘determinant-matching’ conditions. The latter expresses the equality of the Jacobian determinant of the transformation with the one obtained by integrating out the fermions, which so far have been considered only to quadratic terms. We argue that such a restriction is not substantial, as Nicolai maps can be constructed for arbitrary nonlinear sigma models, which feature four-fermion interactions. The fermionic effective one-loop action then gets generalized to higher loops and the perturbative tree expansion of such Nicolai maps receives quantum corrections in the form of fermion loop decorations. The ‘free-action condition’ continues to hold for the classical map, but the ‘determinant-matching condition’ is extended to an infinite hierarchy in fermion loop order. After general considerations for sigma models in four dimensions, we specialize to the case of ℂP N symmetric spaces and construct the associated Nicolai map. These sigma models admit a formulation with only quadratic fermions via an auxiliary vector field, which does not simplify our analysis.

Erika CS Künstler,1,2 Matthias Schwab,1,2 Henry WS Schroeder,3 Sven Rupprecht1,2 1Department of Neurology, Jena University Hospital, Jena, Germany; 2Interdisciplinary Centre for Sleep and Ventilatory Medicine, Jena University Hospital, Jena, Germany; 3Department of Neurosurgery, University Medicine Greifswald, Greifswald, GermanyCorrespondence: Erika CS Künstler, Department of Neurology, Jena University Hospital, Am Klinikum 1, Jena, D-07747, Germany, Tel +49 3641 9323525, Email Erika.Kuenstler@med.uni-jena.deObjective: The pathogenesis of different narcolepsy phenotypes remains unclear. In rare cases, narcolepsy can be attributable to secondary brain pathologies affecting the midbrain. These cases may elucidate the pathological background and the treatment of narcolepsy, but are often limited by poor objective symptom characterization and effects of therapeutic intervention, especially by modern diagnostic standards.Methods: A young adult presented with excessive daytime sleepiness (EDS) that was refractory to classic narcolepsy medication. Diagnosis of narcolepsy was made based on the pathologically shortened sleep latencies in polysomnography and Multiple Sleep Latency Test (MSLT), together with confirmed sleep-onset REM-sleep (SOREM). Preserved hypocretin levels in cerebrospinal fluid, together with the absence of cataplectic events confirmed the diagnosis of narcolepsy type II. MRI revealed a large arachnoid cyst with compression of the midbrain.Results: Six months after fenestration of the cyst, the patient’s EDS had vastly improved. No further SOREM was observed, and polysomnographic and MSLT sleep latencies normalized. No further drug treatment was required.Conclusion: Symptomatic narcolepsy due to space-occupying lesions in the mesencephalon comprises a unique curative treatment option. Here, surgical intervention offers an effective curative therapeutic approach. However, differential diagnosis of symptomatic narcolepsy requires special consideration.Keywords: symptomatic narcolepsy, arachnoid cyst, excessive daytime sleepiness, remission, case report

Abstract Patient‐Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient‐derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, the transcriptomic and chromatin accessibility landscapes of matched colorectal cancer (CRC) PDO, PDX, PDO‐derived PDX (PDOX), and original patient tumors (PT) are compared. Two major remodeling axes are discovered. The first axis delineates PDMC from PT, and the second axis distinguishes PDX and PDO. PDOX are more similar to PDX than PDO, indicating the growth environment is a driving force for chromatin adaptation. Transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX are identified. Among them, KLF14 and EGR2 footprints are enriched in PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient‐derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.

Previous research has identified maladaptive emotion regulation as a key factor in psychopathology. Thus, addressing emotion regulation via scalable, low-threshold digital interventions – such as smartphone-based Cognitive Bias Modification (CBM) – holds important therapeutic potential. Using a randomized-controlled crossover trial, we tested the efficacy of an integrated CBM module within the Affect Regulation Training (ART, i.e., CBM-ART) that targeted emotion regulation through elements of appraisal-based and approach avoidance training.Undergraduate students reporting elevated stress were randomized to a one-week active intervention (Mindgames; including psychoeducation, a quiz, and CBM-ART; n = 40), active control training (Emo Shape; including placebo psychoeducation, a quiz, and a placebo swiping task; n = 36) or waitlist (n = 25). Before and after the intervention, we assessed emotion regulation, interpretation bias, stress and depression. We further tested post-training stress reactivity using an anagram task.Results indicated that the active intervention improved negative (OR = 0.35) and positive (OR = 2.40) interpretation biases and symptom measures (d = 0.52–0.87). However, active control training showed attenuated concurrent pre-post changes on interpretation biases (i.e., OR = 0.53 for negative, and OR = 1.49 for positive interpretations) and symptom measures (d = 0.26–0.91). The active intervention was rated positively in terms of acceptability and usability.These findings provide initial evidence for the efficacy and acceptability of an integrated app-based CBM intervention for emotion regulation in reducing interpretation biases and psychopathological symptoms, including stress. However, future studies should disentangle specific mechanisms underlying interventional effects.

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.

Abstract TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing. We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages. In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.

GRT-X, which targets both the mitochondrial translocator protein (TSPO) and the Kv7.2/3 (KCNQ2/3) potassium channels, has been shown to efficiently promote recovery from cervical spine injury. In the present work, we investigate the role of GRT-X and its two targets in the axonal growth of dorsal root ganglion (DRG) neurons. Neurite outgrowth was quantified in DRG explant cultures prepared from wild-type C57BL6/J and TSPO-KO mice. TSPO was pharmacologically targeted with the agonist XBD173 and the Kv7 channels with the activator ICA-27243 and the inhibitor XE991. GRT-X efficiently stimulated DRG axonal growth at 4 and 8 days after its single administration. XBD173 also promoted axonal elongation, but only after 8 days and its repeated administration. In contrast, both ICA27243 and XE991 tended to decrease axonal elongation. In dissociated DRG neuron/Schwann cell co-cultures, GRT-X upregulated the expression of genes associated with axonal growth and myelination. In the TSPO-KO DRG cultures, the stimulatory effect of GRT-X on axonal growth was completely lost. However, GRT-X and XBD173 activated neuronal and Schwann cell gene expression after TSPO knockout, indicating the presence of additional targets warranting further investigation. These findings uncover a key role of the dual mode of action of GRT-X in the axonal elongation of DRG neurons.

Rapid information processing in the central nervous system requires the myelination of axons by oligodendrocytes. The transcription factor Sox2 and its close relative Sox3 redundantly regulate the development of myelin-forming oligodendrocytes, but little is known about the underlying molecular mechanisms. Here, we characterized the expression profile of cultured oligodendroglial cells during early differentiation and identified Bcas1, Enpp6, Zfp488 and Nkx2.2 as major downregulated genes upon Sox2 and Sox3 deletion. An analysis of mice with oligodendrocyte-specific deletion of Sox2 and Sox3 validated all four genes as downstream targets in vivo. Additional functional assays identified regulatory regions in the vicinity of each gene that are responsive to and bind both Sox proteins. Bcas1, Enpp6, Zfp488 and Nkx2.2 therefore likely represent direct target genes and major effectors of Sox2 and Sox3. Considering the preferential expression and role of these genes in premyelinating oligodendrocytes, our findings suggest that Sox2 and Sox3 impact oligodendroglial development at the premyelinating stage with Bcas1, Enpp6, Zfp488 and Nkx2.2 as their major effectors.

Abstract Background Thrombotic microangiopathy (TMA) is a potentially organ and life-threatening condition affecting patients with multiple myeloma (MM). Cases of proteasome inhibitor-induced TMA and specifically carfilzomib-induced TMA have been rarely reported and standards for diagnostic workup and treatment are not available. Case presentation We describe a case of a male MM patient under salvage therapy including proteasome inhibitor carfilzomib following chemotherapy and autologous stem cell transplantation. The patient then developed acute kidney injury with clinical and laboratory signs of TMA. Hemodialysis became necessary and treatment with plasma exchange was initiated followed by therapy with C5 complement inhibitor eculizumab which led to amelioration of kidney function and hemolysis parameters. Conclusion We report a patient with suspected proteasome inhibitor-induced secondary thrombotic microangiopathy that has been successfully treated with plasma exchange and eculizumab, a monoclonal antibody targeting complement factor C5.

Erika CS Künstler,1,2 Peter Bublak,1 Kathrin Finke,1 Nicolas Koranyi,1 Marie Meinhard,1 Matthias Schwab,1,2 Sven Rupprecht1,2 1Department of Neurology, Jena University Hospital, Jena, Germany; 2Interdisciplinary Centre for Sleep and Ventilatory Medicine, Jena University Hospital, Jena, GermanyCorrespondence: Erika CS Künstler, Department of Neurology, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany, Tel +49 3641 9323525, Email Erika.Kuenstler@med.uni-jena.deStudy Objectives: Persistent insomnia disorder (pID) is linked to neurocognitive decline and increased risk of Alzheimer’s Disease (AD) in later life. However, research in this field often utilizes self-reported sleep quality data - which may be biased by sleep misperception - or uses extensive neurocognitive test batteries - which are often not feasible in clinical settings. This study therefore aims to assess whether a simple screening tool could uncover a specific pattern of cognitive changes in pID patients, and whether these relate to objective aspect(s) of sleep quality.Methods: Neurocognitive performance (Montreal Cognitive Assessment; MoCA), anxiety/depression severity, and subjective sleep quality (Pittsburgh Sleep Quality Index: PSQI; Insomnia Severity Index: ISI) data were collected from 22 middle-aged pID patients and 22 good-sleepers. Patients underwent overnight polysomnography.Results: Compared to good-sleepers, patients had lower overall cognitive performance (average: 24.6 versus 26.3 points, Mann–Whitney U = 136.5, p = < 0.006), with deficits in clock drawing and verbal abstraction. In patients, poorer overall cognitive performance correlated with reduced subjective sleep quality (PSQI: r(42) = − 0.47, p = 0.001; and ISI: r(42) = − 0.43, p = 0.004), reduced objective sleep quality (lower sleep efficiency: r(20) = 0.59, p = 0.004 and less REM-sleep: r(20) = 0.52, p = 0.013; and increased sleep latency: r(20) = − 0.57, p = 0.005 and time awake: r(20) = − 0.59, p = 0.004). Cognitive performance was not related to anxiety/depression scores.Conclusion: Using a simple neurocognitive screening tool, we found that pID patients showed cognitive deficiencies that related to both subjective/self-reported and objective/polysomnographic measures of sleep quality. Furthermore, these cognitive changes resembled those seen in preclinical non-amnestic AD, and thus could indicate incumbent neurodegenerative processes in pID. Interestingly, increased REM-sleep was correlated with better cognitive performance. However, whether REM-sleep is protective against neurodegeneration requires further investigation.Keywords: insomnia, sleep, neurodegeneration, Alzheimer’s disease, polysomnography, cognitive screening

Abstract Rabies is an ancient disease. Two centuries since Pasteur, fundamental progress occurred in virology, vaccinology, and diagnostics—and an understanding of pathobiology and epizootiology of rabies in testament to One Health—before common terminological coinage. Prevention, control, selective elimination, and even the unthinkable—occasional treatment—of this zoonosis dawned by the twenty-first century. However, in contrast to smallpox and rinderpest, eradication is a wishful misnomer applied to rabies, particularly post-COVID-19 pandemic. Reasons are minion. Polyhostality encompasses bats and mesocarnivores, but other mammals represent a diverse spectrum of potential hosts. While rabies virus is the classical member of the genus, other species of lyssaviruses also cause the disease. Some reservoirs remain cryptic. Although global, this viral encephalitis is untreatable and often ignored. As with other neglected diseases, laboratory-based surveillance falls short of the notifiable ideal, especially in lower- and middle-income countries. Calculation of actual burden defaults to a flux within broad health economic models. Competing priorities, lack of defined, long-term international donors, and shrinking local champions challenge human prophylaxis and mass dog vaccination toward targets of 2030 for even canine rabies impacts. For prevention, all licensed vaccines are delivered to the individual, whether parenteral or oral–essentially ‘one and done’. Exploiting mammalian social behaviors, future ‘spreadable vaccines’ might increase the proportion of immunized hosts per unit effort. However, the release of replication-competent, genetically modified organisms selectively engineered to spread intentionally throughout a population raises significant biological, ethical, and regulatory issues in need of broader, transdisciplinary discourse. How this rather curious idea will evolve toward actual unconventional prevention, control, or elimination in the near term remains debatable. In the interim, more precise terminology and realistic expectations serve as the norm for diverse, collective constituents to maintain progress in the field.

The use of the Experience Sampling Method (ESM), which involves repeated assessments in people’s daily lives, has increased in popularity in psychology and associated disciplines in recent years. A rather challenging aspect of ESM is its technical implementation. In this paper, after briefly introducing the history of ESM and the main reasons for its current popularity, we outline the ESM-Quest experience sampling app which is currently being developed at the University of Vienna. ESM-Quest runs on different operating systems, specifically on mobile devices such as smartphones and tablets running either iOS or Android. An internet connection is not necessary during the assessment. Compared to most other ESM apps, ESM-Quest allows event-based random sampling, which is very helpful when assessments need to be collected within specific situations. Currently, ESM-Quest is being utilized at the University of Vienna and will be made available for research groups worldwide upon request. We introduce the technical aspects of ESM-Quest and provide examples of analyses on ESM data collected through this app, such as examining fluctuations in constructs within individuals. Finally, we outline potential next steps in ESM research.

Background: Biomedical knowledge graphs (KG) have become crucial for describing biological findings in a structured manner. To keep up with the constantly changing flow of knowledge, their embedded information must be regularly updated with the latest findings. Natural language processing (NLP) has created new possibilities for automating this upkeep by facilitating information extraction from free text. However, due to annotated and labeled biomedical data limitations, the development of completely autonomous information extraction systems remains a substantial scientific and technological hurdle. This study aims to explore methodologies best suited to support the automatic extraction of causal relationships from biomedical literature with the aim of regular and rapid updating of disease-specific pathophysiology mechanism KGs. Methods: Our proposed approach first searches and retrieves PubMed abstracts using the desired terms and keywords. The extension corpora are then passed through the NLP pipeline for automatic information extraction. We then identify triples representing cause-and-effect relationships and encode this content using the Biological Expression Language (BEL). Finally, domain experts perform an analysis of the completeness, relevance, accuracy, and novelty of the extracted triples. Results: In our test scenario, which is focused on the KG regarding the phosphorylation of the Tau protein, our pipeline successfully contributed novel data, which was then subsequently used to update the KG leading to the identification of six additional upstream regulators of Tau phosphorylation. Conclusion: Here, it is demonstrated that the NLP-based workflow we created is capable of rapidly updating pathophysiology mechanism graphs. As a result, production-scale, semi-automated updating of pre-existing, curated mechanism graphs is enabled.

BackgroundNeurosteroids have recently gained in interest as a treatment strategy for affective disorders. Etifoxine is known for its dual mode of action, one of which is to stimulate endogenous neurosteroid synthesis. The gut microbiome has been studied in affective disorders, but it has not been investigated in the context of human etifoxine or neurosteroid interventions.MethodsWe performed a crossover study with 36 healthy male volunteers who received etifoxine versus alprazolam and placebo in a balanced Williams design. Participants were randomized into six sequences and went through three 5-day treatments followed by wash-out phases of 9 days. Bacterial compositions in stool samples were determined by high-throughput 16S rRNA amplicon sequencing.ResultsGut microbiome analyses revealed no relevant effects between treatments with respect to alpha and beta diversity. Differential abundance analyses yielded etifoxine treatment as the only effect related to changes in microbial features with reductions of Faecalibacterium duncaniae, Roseburia hominis and Lactobacillus rogosae (i.e., Bacteroides galacturonicus).ConclusionHere we report on the first human investigation of the gut microbiome with short-term etifoxine intervention. Differences in diversity and compositional structure of the microbiome were more likely due to between- subject effects rather than medication. However, five-day treatment with etifoxine reduced the abundance of a few bacterial species. These species are currently seen as beneficial components of a healthy intestinal microbiome. This reduction in abundances may be related to elevated endogenous neurosteroids.

Introduction: Large datasets are required to ensure reliable non-invasive glioma assessment with radiomics-based machine learning methods. This can often only be achieved by pooling images from different centers. Moreover, trained models should perform with high accuracy when applied to data from different centers. In this study, the impact of reconstruction settings and segmentation methods on radiomic features derived from amino acid and TSPO PET images of glioma patients was examined. Additionally, the ability to model and thus reduce feature differences was investigated. Methods: [18F]FET and [18F]GE-180 PET data were acquired from 19 glioma patients. For each acquisition, 10 reconstruction settings and 9 segmentation methods were included to emulate multicentric data. Statistical robustness measures were calculated before and after ComBat harmonization. Differences between features due to setting variations were assessed using Friedman test, coefficient of variation (CV) and inter-rater reliability measures, including intraclass and Spearman’s rank correlation coefficients and Fleiss’ Kappa. Results: According to Friedman analyses, most features (>60%) showed significant differences. Yet, CV and inter-rater reliability measures indicated higher robustness. ComBat resulted in almost complete harmonization (>87%) according to Friedman test and little to no improvement according to CV and inter-rater reliability measures. [18F]GE-180 features were more sensitive to reconstruction settings than [18F]FET features. Conclusions: According to Friedman test, feature distributions could be successfully aligned using ComBat. However, depending on settings, changes in patient ranks were observed for some features and could not be eliminated by harmonization. Thus, for clinical utilization it is recommended to exclude affected features.

Abstract In this work, we present a novel approach to photothermal super resolution based thermographic resolution of internal defects using two-dimensional pixel pattern-based active photothermal laser heating in conjunction with subsequent numerical reconstruction to achieve a high-resolution reconstruction of internal defect structures. With the proposed adoption of pixelated patterns generated using laser coupled high-power DLP projector technology the complexity for achieving true two-dimensional super resolution can be dramatically reduced taking a crucial step forward towards widespread practical viability. Furthermore, based on the latest developments in high-power DLP projectors, we present their first application for structured pulsed thermographic inspection of macroscopic metal samples. In addition, a forward solution to the underlying inverse problem is proposed along with an appropriate heuristic to find the regularization parameters necessary for the numerical inversion in a laboratory setting. This allows the generation of synthetic measurement data, opening the door for the application of machine learning based methods for future improvements towards full automation of the method. Finally, the proposed method is experimentally validated and shown to outperform several established conventional thermographic testing techniques while conservatively improving the required measurement times by a factor of 8 compared to currently available photothermal super resolution techniques.

Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available.

Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.

Summary: Lamin A/C is a well-established key contributor to nuclear stiffness and its role in nucleus mechanical properties has been extensively studied. However, its impact on whole-cell mechanics has been poorly addressed, particularly concerning measurable physical parameters. In this study, we combined microfluidic experiments with theoretical analyses to quantitatively estimate the whole-cell mechanical properties. This allowed us to characterize the mechanical changes induced in cells by lamin A/C alterations and prelamin A accumulation resulting from atazanavir treatment or lipodystrophy-associated LMNA R482W pathogenic variant. Our results reveal a distinctive increase in long-time viscosity as a signature of cells affected by lamin A/C alterations. Furthermore, they show that the whole-cell response to mechanical stress is driven not only by the nucleus but also by the nucleo-cytoskeleton links and the microtubule network. The enhanced cell viscosity assessed with our microfluidic assay could serve as a valuable diagnosis marker for lamin-related diseases.

Abstract Objectives The purpose of this study was to investigate whether the addition of computed tomography (CT) to magnetic resonance imaging (MRI) improves the accuracy of classifying osteoporotic vertebral body fractures (OVBF). Methods A retrospective analysis of a prospective single-center database has been performed. All consecutive patients who had suffered an acute thoracolumbar OVBF in one level II spine center between 2017 and 2019 were analyzed. Thereby, fractures of type OF 1 and OF 5 were excluded. All fractures were initially classified by 5 board-certified orthopaedic surgeons based on MRI and conventional radiographs. Afterwards a reclassification including CT scans were performed. Differences in OF classification and OF score values between both measurements were analyzed. Results A total of 61 patients were analyzed with a mean age 75.8 years (SD: 8.8 years). In 82.9% of the cases, there was no difference in OF classification comparing classification based only on MRI versus MRI + CT. A difference of more than two OF types was observed in less than 1% of all ratings. The inter-rater reliabilities of the OF classification based on CT + MRI and MRI alone were 0.63 and 0.49, respectively. In 97.5% of the cases there was no therapy-relevant difference of the treatment recommendation with respect of a surgical or nonoperative treatment recommendation based on the OF score. Conclusion In terms of the OF classification and the OF score, the addition of CT add limited value compared to conventional radiographs and MRI only. Additionally, there is only a minor rate of disagreement in treatment recommendations when adding a CT.

The COVID-19 pandemic has disrupted everyday living and social practices, prompting questions of whether more sustainable consumption patterns are emerging and the likelihood of their long-term retention. To examine these questions, we apply a practice-based approach to a quantitative study of COVID-driven practice changes in the domains of food, material consumption, housing, and mobility conducted in four global North countries (Germany, Italy, Japan, and the United States). We discuss the trends emerging from our analysis from a sustainability perspective and address the role of social practice elements – materials, meanings, competences – in the establishment and discontinuation of sustainable consumption practices. Observed sustainability gains in specific practices and domains (such as a decrease in material consumption and more sustainable food practices and diets), may be offset by other practices, particularly a renewed desire for air travel and larger housing. The uptake and lock-in of sustainable practices are driven by a combination of meaning and material-related practice elements such as the alignment with interests and personal values; the availability of labor, energy, or time; and the ability to routinize practices. However, new policies to support emerging lifestyle shifts, as well as the development of businesses catering to and encouraging low-impact practices, may ultimately determine the formation of a more sustainable “new normal.” We also reflect on the strengths and limitations of using quantitative research methods in studies of sustainable consumption informed by social practice theories.

Abstract The Nicolai map is a field transformation that relates supersymmetric theories at finite couplings g with the free theory at g = 0. It is obtained via an ordered exponential of the coupling flow operator integrated from 0 to g. Allowing multiple couplings, we find that the map in general depends on the chosen integration contour in coupling space. This induces a large functional freedom in the construction of the Nicolai map, which cancels in all correlator computations. Under a certain condition on the coupling flow operator the ambiguity disappears, and the power-series expansion for the map collapses to a linear function in the coupling. A special role is played by topological (theta) couplings, which do not affect perturbative correlation functions but also alter the Nicolai map. We demonstate that for certain ‘magical’ theta values the uniqueness condition holds, providing an exact map polynomial in the fields and independent of the integration contour. This feature is related to critical points of the Nicolai map and the existence of ‘instantons’. As a toy model, we work with N $$ \mathcal{N} $$ = 1 supersymmetric quantum mechanics. For a cubic superpotential and a theta term, we explicitly compute the one-, two- and three-point correlation function to one-loop order employing a graphical representation of the (inverse) Nicolai map in terms of tree diagrams, confirming the cancellation of theta dependence. Comparison of Nicolai and conventional Feynman perturbation theory nontrivially yields complete agreement, but only after adding all (1PI and 1PR) contributions.

BackgroundAnxiety and depressive disorders share common features of mood dysfunctions. This has stimulated interest in transdiagnostic dimensional research as proposed by the Research Domain Criteria (RDoC) approach by the National Institute of Mental Health (NIMH) aiming to improve the understanding of underlying disease mechanisms. The purpose of this study was to investigate the processing of RDoC domains in relation to disease severity in order to identify latent disorder-specific as well as transdiagnostic indicators of disease severity in patients with anxiety and depressive disorders.MethodsWithin the German research network for mental disorders, 895 participants (n = 476 female, n = 602 anxiety disorder, n = 257 depressive disorder) were recruited for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) and included in this cross-sectional study. We performed incremental regression models to investigate the association of four RDoC domains on disease severity in patients with affective disorders: Positive (PVS) and Negative Valance System (NVS), Cognitive Systems (CS) and Social Processes (SP).ResultsThe results confirmed a transdiagnostic relationship for all four domains, as we found significant main effects on disease severity within domain-specific models (PVS: β = −0.35; NVS: β = 0.39; CS: β = −0.12; SP: β = −0.32). We also found three significant interaction effects with main diagnosis showing a disease-specific association.LimitationsThe cross-sectional study design prevents causal conclusions. Further limitations include possible outliers and heteroskedasticity in all regression models which we appropriately controlled for.ConclusionOur key results show that symptom burden in anxiety and depressive disorders is associated with latent RDoC indicators in transdiagnostic and disease-specific ways.

Although hundreds of datasets have been published since the beginning of the coronavirus pandemic, there is a lack of centralized resources where these datasets are listed and harmonized to facilitate their applicability and uptake by predictive modeling approaches. Firstly, such a centralized resource provides information about data owners to researchers who are searching datasets to develop their predictive models. Secondly, the harmonization of the datasets supports simultaneously taking advantage of several similar datasets. This, in turn, does not only ease the imperative external validation of data-driven models but can also be used for virtual cohort generation, which helps to overcome data sharing impediments. Here, we present that the COVID-19 data catalogue is a repository that provides a landscape view of COVID-19 studies and datasets as a putative source to enable researchers to develop personalized COVID-19 predictive risk models. The COVID-19 data catalogue currently contains over 400 studies and their relevant information collected from a wide range of global sources such as global initiatives, clinical trial repositories, publications, and data repositories. Further, the curated content stored in this data catalogue is complemented by a web application, providing visualizations of these studies, including their references, relevant information such as measured variables, and the geographical locations of where these studies were performed. This resource is one of the first to capture, organize, and store studies, datasets, and metadata related to COVID-19 in a comprehensive repository. We believe that our work will facilitate future research and development of personalized predictive risk models for COVID-19.

The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria’s involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD’s pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient (“Non-R”) and another with an unexplained mitochondrial disorder (“Mito”). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient’s data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient’s data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.

The complex effects of combined CDki/SPyADI application on arginine-auxotrophic glioblastoma multiforme cells. CDki/SPyADI combination therapy impairs cell proliferation, invasiveness, gene expression, induces mitochondrial impairment, and vacuole formation. Abemaciclib-SPyADI-treatment suppresses DNA repair, dinaciclib-SpyADI-treatment enhances γ-H2AX accumulation and activates the stress sensor GADD45 and β-catenin antagonist AXIN2. Both CDKi/SpyADI combinations significantly boost cell death.

Here, the authors show brightening of dark excitons by strong coupling between cavity photons and high energy, spin-allowed, bright excitons in monolayer WSe2. In this regime, the commonly observed photoluminescence quenching stemming from the fast relaxation to the dark ground state is prevented.

Dog vaccination is an effective rabies prevention measure, but widespread vaccination campaigns are challenging in settings like India with large free-roaming dog populations. Here, the authors describe a One Health campaign in Goa state which led to a large reduction of cases in dogs and elimination in humans.

The transition to a low-carbon energy source from coal has become imperative to mitigating the escalating climate change crisis. This study aims to investigate the organic-rich shale core samples of the Limpopo-Area Karoo Basin, retrieved from the borehole at depth 480–580 m. These samples were subjected to petrographic, mineralogical, morphological, and kerogen-type analysis to investigate potentials for shale gas generation. The petrographic analysis reveals maceral group mainly comprised of vitrinite group with some liptinite and inertinite and mineral compositions. The preponderance of pyrite framboids (1.6–12%) indicate redox of FeS2 as a precursor to methane gas generation in anoxic condition. The x-ray diffractometer (XRD) reveals the presence of quartz, albite, microcline, dolomite, pyrite and clay minerals which alluded to the mineral composition indicated by the petrographic analysis. The clay mineral component consists of montmorillonite, illite, chlorite, and mixed layered illite/smectite (I/S) in the Madzaringwe samples. The representative scanning electron microscopy-Energy Dispersive X-ray (SEM-EDX) images of the studied shales depict a combination of organic-matter, groundmass mineral, micro-fracture pore structures reflecting polyframboidal pyrite and carbonate dissolution morphology. The total organic carbon (TOC) contents averaging at 47 wt%, indicating an excellent source rock. The Rock-Eval 6 programmed pyrolysis samples showed S2 value (15.25–16.47 mg HC/g rock) with an average of 15.69 mg HC/g rock and Hydrogen index (HI) (34.0–37.0 mg HC/g TOC) indicating a Type-III Kerogen dominance prone to gas generation. The shale showed Tmax values (464–470 °C) averaging at 467.2 °C, yielding a thermally mature condensate wet-gas. This study reveals that the Permian carbonaceous rock tends to generate gas which can be hosted mainly by the organic matter pore structures, inorganic and micro-fracture pore structures.

Summary: Recent research suggests that mindfulness, compassion, and self-compassion relate to inner transformative qualities/capacities and intermediary factors that can support increased pro-environmental behavior and attitudes across individual, collective, organizational, and system levels. However, current insights focus on the individual level, are restricted to certain sustainability fields, and wider experimental evidence is scarce and contradictory. Our pilot study addresses this gap and tests the aforementioned proposition in the context of an intervention: an EU Climate Leadership Program for high-level decision-makers. The intervention was found to have significant effects on transformative qualities/capacities, intermediary factors, and pro-environmental behaviors and engagement across all levels. The picture is, however, more complex for pro-environmental attitudes. With due limitations (e.g., small sample size), this preliminary evidence confirms the feasibility and potential of mindfulness- and compassion-based interventions to foster inner-outer transformation for sustainability and climate action. Aspects that should be taken into account in larger confirmatory trials are discussed.

Adding a topological theta term to the action of N=1 D=4 super Yang–Mills theory modifies its Nicolai map. For the BPS value of the theta angle a chiral version of the map emerges, which allows for a considerable simplification compared to the non-chiral formulation. We exhibit these improvements to all orders in perturbation theory and compute the map to fourth order in the coupling on the Laudau-gauge hypersurface. The second-order contribution vanishes, and antisymmetrizations are more manifest. All checks are verified to third order.

Canine-mediated rabies kills tens of thousands of people annually in lesser-developed communities of Asia, Africa, and the Americas, primarily through bites from infected dogs. Multiple rabies outbreaks have been associated with human deaths in Nigeria. However, the lack of quality data on human rabies hinders advocacy and resource allocation for effective prevention and control. We obtained 20 years of dog bite surveillance data across 19 major hospitals in Abuja, incorporating modifiable and environmental covariates. To overcome the challenge of missing information, we used a Bayesian approach with expert-solicited prior information to jointly model missing covariate data and the additive effects of the covariates on the predicted probability of human death after rabies virus exposure. Only 1155 cases of dog bites were recorded throughout the study period, out of which 4.2% (N = 49) died of rabies. The odds for risk of human death were predicted to decrease among individuals who were bitten by owned dogs compared to those bitten by free-roaming dogs. Similarly, there was a predicted decrease in the probability of human death among victims bitten by vaccinated dogs compared to those bitten by unvaccinated dogs. The odds for the risk of human death after bitten individuals received rabies prophylaxis were predicted to decrease compared to no prophylaxis. We demonstrate the practical application of a regularised Bayesian approach to model sparse dog bite surveillance data to uncover risk factors for human rabies, with broader applications in other endemic rabies settings with similar profiles. The low reporting observed in this study underscores the need for community engagement and investment in surveillance to increase data availability. Better data on bite cases will help to estimate the burden of rabies in Nigeria and would be important to plan effective prevention and control of this disease.

Abstract We offer a novel perspective on N $$ \mathcal{N} $$ = 4 supersymmetric Yang-Mills (SYM) theory through the framework of the Nicolai map, a transformation of the bosonic fields that allows one to compute quantum correlators in terms of a free, purely bosonic functional measure. Generally, any Nicolai map is obtained through a path-ordered exponential of the so-called coupling flow operator. The latter can be canonically constructed in any gauge using an N $$ \mathcal{N} $$ = 1 off-shell superfield formulation of N $$ \mathcal{N} $$ = 4 SYM, or alternatively through dimensional reduction of the result from N $$ \mathcal{N} $$ = 1 D = 10 SYM, in which case we need to restrict to the Landau gauge. We propose a general theory of the N $$ \mathcal{N} $$ = 4 coupling flow operator, arguing that it exhibits an ambiguity in form of an R-symmetry freedom given by the Lie algebra su $$ \mathfrak{su} $$ (4). This theory incorporates our two construction approaches as special points in su $$ \mathfrak{su} $$ (4) and defines a broad class of Nicolai maps for N $$ \mathcal{N} $$ = 4 SYM.

Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin N-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds.

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97–40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 μg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 μg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation.

Here, the authors show that the interaction between microcavity photons and excitons in an atomically thin WSe2 results in a hybridized regime of strong light-matter coupling. Coherence build-up is accompanied by a threshold-like behaviour of the emitted light intensity, which is a fingerprint of a polariton laser effect.

Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput chemical screens with patient-derived models of cancer to identify new potential therapeutic targets for CRC. However, this pipeline is limited by (1) the use of cell lines that do not appropriately recapitulate the tumor microenvironment, and (2) the use of patient-derived xenografts (PDXs), which are time-consuming and costly for validation of drug efficacy. To overcome these limitations, we have turned to patient-derived organoids. Organoids are increasingly being accepted as a “standard” preclinical model that recapitulates tumor microenvironment cross-talk in a rapid, cost-effective platform. In the present work, we employed a library of natural products, intermediates, and drug-like compounds for which full synthesis has been demonstrated. Using this compound library, we performed a high-throughput screen on multiple low-passage cancer cell lines to identify potential treatments. The top candidate, psymberin, was further validated, with a focus on CRC cell lines and organoids. Mechanistic and genomics analyses pinpointed protein translation inhibition as a mechanism of action of psymberin. These findings suggest the potential of psymberin as a novel therapy for the treatment of CRC.