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Background: Current standard methods in monitoring glaucoma progression, like optical coherence tomography (OCT) and standard automated perimetry (SAP), have limitations in certain cases. Automated relative afferent pupillary defect (RAPD) and pupillary light reflex (PLR) testing may offer more objective alternatives. This pilot study aimed to evaluate whether RAPD could sufficiently distinguish between the two eyes in asymmetrical glaucoma, and thus could lay the foundation for using the PLR of a single eye to monitor progression longitudinally., Methods: Twenty-one patients underwent quantitative PLR measurements using a virtual reality headset. RAPD was calculated by subtracting the amplitude of PLRs between eyes. Both RAPD and relative SAP (measured using the mean defect or MD) results were correlated to the thickness of the peripapillary retinal nerve fiber layer (RNFL), as measured by OCT., Results: Data from 18 patients was analyzed after exclusions. RAPD significantly correlated with differences between the two eyes as measured by RNFL thickness (Pearson r = 0.79, p = 0.05). MD differences correlated slightly better with RNFL differences (Pearson r = 0.87, p < 0.05). RAPD and MD combined yielded an improved prediction of RNFL differences by 5% compared to using MD only., Conclusions: RAPD measurements reliably detected asymmetries in optic nerve damage in glaucoma patients. SAP measurements correlated better with OCT results than RAPD results. However, SAP and RAPD combined led to an improved prediction of RNFL thickness. This could possibly allow us to use PLR only over longer periods of time to monitor glaucomatous optic nerve damage in a single eye in the future., Competing Interests: Mathias Abegg, Avantika Naidu and Bruno Hauser are employees of the company machineMD. Mathias Abegg is a shareholder of the company machineMD. machineMD is the manufacturer of the medical device neos, which was used for the measurements in this study. The significance of pupils for glaucoma investigated in the study presented here does not play a role in either the current or planned future versions of neos., (Thieme. All rights reserved.)

The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. Our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are promising, synthetically tractable antimalarials., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The precise function of specialized GABAergic interneuron subtypes is required to provide appropriate synaptic inhibition for regulating principal neuron excitability and synchronization within brain circuits. Of these, parvalbumin-type (PV neuron) dysfunction is a feature of several sex-biased psychiatric and brain disorders, although, the underlying developmental mechanisms are unclear. While the transcriptional action of sex hormones generates sexual dimorphism during brain development, whether kinase signaling contributes to sex differences in PV neuron function remains unexplored. In the hippocampus, we report that gephyrin, the main inhibitory post-synaptic scaffolding protein, is phosphorylated at serine S268 and S270 in a developmentally-dependent manner in both males and females. When examining Gphn S268A/S270A mice in which site-specific phosphorylation is constitutively blocked, we found that sex differences in PV neuron density in the hippocampal CA1 present in WT mice were abolished, coincident with a female-specific increase in PV neuron-derived terminals and increased inhibitory input onto principal cells. Electrophysiological analysis of CA1 PV neurons indicated that gephyrin phosphorylation is required for sexually dimorphic function. Moreover, while male and female WT mice showed no difference in hippocampus-dependent memory tasks, Gphn S268A/S270A mice exhibited sex- and task-specific deficits, indicating that gephyrin phosphorylation is differentially required by males and females for convergent cognitive function. In fate mapping experiments, we uncovered that gephyrin phosphorylation at S268 and S270 establishes sex differences in putative PV neuron density during early postnatal development. Furthermore, patch-sequencing of putative PV neurons at postnatal day 4 revealed that gephyrin phosphorylation contributes to sex differences in the transcriptomic profile of developing interneurons. Therefore, these early shifts in male-female interneuron development may drive adult sex differences in PV neuron function and connectivity. Our results identify gephyrin phosphorylation as a new substrate organizing PV neuron development at the anatomical, functional, and transcriptional levels in a sex-dependent manner, thus implicating kinase signaling disruption as a new mechanism contributing to the sex-dependent etiology of brain disorders., (© 2024. The Author(s).)

Four yeast isolates were obtained from rotting wood and galleries of passalid beetles collected in different sites of the Brazilian Amazonian Rainforest in Brazil. This yeast produces unconjugated allantoid asci each with a single elongated ascospore with curved ends. Sequence analysis of the internal transcribed spacer-5.8 S region and the D1/D2 domains of the large subunit ribosomal RNA (rRNA) gene showed that the isolates represent a novel species of the genus Spathaspora. The novel species is phylogenetically related to a subclade containing Spathaspora arborariae and Spathaspora suhii. Phylogenomic analysis based on 1884 single-copy orthologs for a set of Spathaspora species whose whole genome sequences are available confirmed that the novel species represented by strain UFMG-CM-Y285 is phylogenetically close to Sp. arborariae. The name Spathaspora marinasilvae sp. nov. is proposed to accommodate the novel species. The holotype of Sp. marinasilvae is CBS 13467  T (MycoBank 852799). The novel species was able to accumulate xylitol and produce ethanol from  d-xylose, a trait of biotechnological interest common to several species of the genus Spathaspora., (© 2024 John Wiley & Sons Ltd.)

Studying synapses in vivo presents challenges due to the complexity of accurately targeting and visualizing specific synaptic proteins within the brain. Here, we present a protocol for in vivo analysis of pre- and post-synaptic protein function in mice. We describe steps for combining adeno-associated virus (AAV)-mediated gene transfer to manipulate specific neuron subtypes. We also describe immunofluorescence on artificial cerebrospinal fluid (ACSF)-perfused brain sections to enhance the visualization of synaptic proteins. For complete details on the use and execution of this protocol, please refer to Cramer et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Estimating growing stock is one of the main objectives of forest inventories. It refers to the stem volume of individual trees which is typically derived by models as it cannot be easily measured directly. These models are thus based on measurable tree dimensions and their parameterization depends on the available empirical data. Historically, such data were collected by measurements of tree stem sizes, which is very time- and cost-intensive. Here, we present an exceptionally large dataset with section-wise stem measurements on 40'349 felled individual trees collected on plots of the Experimental Forest Management project. It is a revised and expanded version of previously unpublished data and contains the empirically derived coarse (diameter ≥7 cm) and fine branch volume of 27'297 and 18'980, respectively, individual trees. The data were collected between 1888 and 1974 across Switzerland covering a large topographic gradient and a diverse species range and can thus support estimations and verification of volume functions also outside Switzerland including the derivation of whole tree volume in a consistent manner., (© 2024. The Author(s).)

Forensic anthropology (FA) as a specialized discipline has been practised in multi-lingual Switzerland for over a decade. A variety of expertise regarding osteological assessments as well as facial image comparison (FIC) is provided by different centres. Nevertheless, information is lacking about the awareness of FA and its benefits for forensic investigations among forensic stakeholders. Therefore, a survey was sent to Swiss anthropologists (AN) and related professions (police officers, prosecutors, and forensic pathologists) to assess three main aspects: (1) the experience of working (biological/forensic) anthropologists within FA; (2) how FA is perceived by other professions within the legal system; and (3) identify gaps (if any) in understanding of FA with the aim to suggest avenues for improvement if necessary. The results show that awareness of FA varies by occupation and cantonal regions. In areas where close collaborations between forensic anthropologists (FAs) and other stakeholders have been formally established, be it with focus on osteological analyses or FIC, the awareness of FA competencies was superior to areas where this was not the case. An overwhelming majority of forensic actors expressed interest in continuing education related to the role of FA. These findings indicate that facilitation of communication and collaboration leads to improvement in the awareness of the competencies of FAs and their contribution to forensic investigations., (© 2023. The Author(s).)

As a vital micronutrient, zinc is integral to the structure, function, and signaling networks of diverse proteins. Dysregulated zinc levels, due to either excess intake or deficiency, are associated with a spectrum of health disorders. In this context, understanding zinc-regulated biological processes at the molecular level holds significant relevance to public health and clinical practice. Identifying and characterizing zinc-regulated proteins in their diverse proteoforms, however, remain a difficult task in advancing zinc biology. Herein, we address this challenge by developing a quantitative chemical proteomics platform that globally profiles the reactivities of proteinaceous cysteines upon cellular zinc depletion. Exploiting a protein-conjugated resin for the selective removal of Zn 2+ from culture media, we identify an array of zinc-sensitive cysteines on proteins with diverse functions based on their increased reactivity upon zinc depletion. Notably, we find that zinc regulates the enzymatic activities, post-translational modifications, and subcellular distributions of selected target proteins such as peroxiredoxin 6 (PRDX6), platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3), and phosphoglycerate kinase (PGK1).

Summer skiing on glaciers is a leisure activity highly dependent on natural factors like weather and glacier conditions. While the literature agrees that climate change is shaping the fate of summer skiing, longer time series covering both the supply and demand side of glacier/summer skiing, and research that combines natural and non-natural factors affecting the summer ski market are missing. To close this research gap, we conducted a detailed supply-side analysis of nine Austrian glacier ski areas focusing on the number of operating days (in the summer half-year, as well as for meteorological and astronomical summer ski definitions), show how these numbers evolve over time, test how they correlate with meteorological and glaciological data using time-series regression models on a yearly and monthly basis, and highlight how managerial decisions come into play when trying to explain the summer ski supply's decline. Between 2002 and 2019, summer ski operating days in Austrian glacier ski areas declined by 48.3% in the summer half-year, 65.2% in the meteorological, and 62.3% in the astronomical summer parallel to rising mean temperatures and shrinking glaciers. This decrease is strongest in June to September and weakest in May and October but in two glacier ski areas, the operating days in the summer season remain constant or are even on the rise. This is in line with model results indicating that meteorological and glaciological data only explain parts of the variance of the decline trends. Operators' agency, strategies, and decisions play an important role underlining that global warming is not monocausally determining summer ski operation., (© 2022. The Author(s).)

Rising air temperatures threaten the snow reliability of ski resorts. Most resorts rely on technical snowmaking to compensate lacking natural snow. But increased water consumption for snowmaking may cause conflicts with other sectors' water uses such as hydropower production or the hotel industry. We assessed the future snow reliability (likelihood of a continuous 100-day skiing season and of operable Christmas holidays) of the Swiss resort Andermatt-Sedrun-Disentis throughout the twenty-first century, where 65% of the area is currently equipped for snowmaking. Our projections are based on the most recent climate change scenarios for Switzerland (CH2018) and the model SkiSim 2.0 including a snowmaking module. Unabated greenhouse gas emissions (scenario RCP8.5) will cause a lack of natural snow at areas below 1800-2000 m asl by the mid-twenty-first century. Initially, this can be fully compensated by snowmaking, but by the end of the century, the results become more nuanced. While snowmaking can provide a continuous 100-day season throughout the twenty-first century, the economically important Christmas holidays are increasingly at risk under the high-emission scenario in the late twenty-first century. The overall high snow reliability of the resort comes at the cost of an increased water demand. The total water consumption of the resort will rise by 79% by the end of the century (2070-2099 compared to 1981-2010; scenario RCP8.5), implying that new water sources will have to be exploited. Future water management plans at the catchment level, embracing the stakeholders, could help to solve future claims for water in the region., (© 2022. The Author(s).)

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiwell plates are prominent in the biological and chemical sciences; however, they face limitations in terms of throughput and deployment in emerging bioengineering fields. Droplet microarrays, as an open microfluidic technology, organise tiny droplets typically in the order of thousands, on an accessible plate. In this perspective, we summarise current approaches for generating droplets, fluid handling on them, and analysis within droplet microarrays. By enabling unique plate engineering opportunities, demonstrating the necessary experimental procedures required for manipulating and interacting with biological cells, and integrating with label-free analytical techniques, droplet microarrays can be deployed across a more extensive experimental domain than what is currently covered by multiwell plates. Droplet microarrays thus offer a solution to the bottlenecks associated with multiwell plates, particularly in the areas of biological cultivation and high-throughput compound screening.

Gephyrin is the main scaffolding protein at inhibitory postsynaptic sites, and its clusters are the signaling hubs where several molecular pathways converge. Post-translational modifications (PTMs) of gephyrin alter GABA A receptor clustering at the synapse, but it is unclear how this affects neuronal activity at the circuit level. We assessed the contribution of gephyrin PTMs to microcircuit activity in the mouse barrel cortex by slice electrophysiology and in vivo two-photon calcium imaging of layer 2/3 (L2/3) pyramidal cells during single-whisker stimulation. Our results suggest that, depending on the type of gephyrin PTM, the neuronal activities of L2/3 pyramidal neurons can be differentially modulated, leading to changes in the size of the neuronal population responding to the single-whisker stimulation. Furthermore, we show that gephyrin PTMs have their preference for selecting synaptic GABA A receptor subunits. Our results identify an important role of gephyrin and GABAergic postsynaptic sites for cortical microcircuit function during sensory stimulation., (© 2024. The Author(s).)

Photolipids have emerged as attractive tools for the optical control of lipid functions. They often contain an azobenzene photoswitch that imparts a cis double-bond upon irradiation. Herein, we present the application of photoswitching to a lipidated natural product, the potent proteasome inhibitor cepafungin I. Several azobenzene-containing lipids were attached to the cyclopeptide core, yielding photoswitchable derivatives. Most notably, PhotoCep4 exhibited a 10-fold higher cellular potency in its light-induced cis-form, matching the potency of natural cepafungin I. The length of the photolipid tail and distal positioning of the azobenzene photoswitch with respect to the macrocycle is critical for this activity. In a proteome-wide experiment, light-triggered PhotoCep4 modulation showed high overlap with constitutively active cepafungin I. The mode of action was studied using crystallography and revealed an identical binding of the cyclopeptide in comparison to cepafungin I, suggesting that differences in their cellular activity originate from switching the tail structure. The photopharmacological approach described herein could be applicable to many other natural products as lipid conjugation is common and often necessary for potent activity. Such lipids are often introduced late in synthetic routes, enabling facile chemical modifications., (© 2023 Wiley-VCH GmbH.)

α-Synuclein is an important drug target for the treatment of Parkinson's disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5' untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5' UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient-derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders., Competing Interests: Competing interests statement:M.D.D. is a founder of Expansion Therapeutics. M.M.M. is a founder of MentiNova.

Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system 1 . Remote-sensing estimates to quantify carbon losses from global forests 2-5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced 6 and satellite-derived approaches 2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151-363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea 2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets., (© 2023. The Author(s).)

Small molecules that target RNA and effect their cleavage are useful chemical probes and potential lead medicines. In this study, we investigate factors affecting degradation of two cancer-associated RNA targets, the mRNA that encodes the transcription factor JUN (c-Jun) and the hairpin precursor to microRNA-372 (pre-miR-372). The two RNA targets harbor the same small-molecule binding site juxtaposed with different neighboring structures. Specifically, pre-miR-372 has AU pairs and contiguous purines on one strand near the small-molecule binding site, making it an ideal substrate for oxidative cleavage via the direct degrader bleomycin A5. In contrast, while JUN mRNA has a similar number of AU pairs near the small-molecule binding site, it lacks contiguous purine nucleotides. Instead, it contains unpaired pyrimidine nucleotides, which are preferred substrates for RNase L, a ribonuclease that can be recruited to RNA with heterobifunctional ribonuclease targeting chimeras (RiboTACs). We hypothesized that structural features surrounding the binding site could be leveraged to program selective small-molecule degradation by alteration of the cleaving module. Indeed, the bleomycin degrader cleaves pre-miR-372 in gastric cancer cells but not JUN mRNA. Conversely, the RiboTAC cleaves JUN mRNA but not pre-miR-372. Thus, the selection of the appropriate cleaving effector moiety for an RNA-binding small molecule can be leveraged to cleave an RNA selectively in a predictable manner, which could have broad implications.

Virtual Anthropology (VA) transposes the traditional methods of physical anthropology to virtual environments using imaging techniques and exploits imaging technologies to devise new methodological protocols. In this research, we investigate whether the measurements used in the Diagnose Sexuelle Probabiliste (DSP) and Ischio-Pubic Index (IPI) differ significantly when 3D models of a bone are generated using 3D surface scans (3DSS) and Multidetector Computed Tomography (MDCT) scans. Thirty pelvises were selected from the SIMON identified skeletal collection. An equal ratio of females to males was sought, as well as a good preservation of the bones. The pelvises were scanned using an MDCT scanner and a 3D surface scanner. The measurements of the DSP and IPI methods on the dry bones (referred to as macroscopic measurements here), and then to the 3D models. The intra- and interobserver, using the Technical Error of Measurement (TEM) and relative Technical Error of Measurement (rTEM) error was assessed, and we aimed to observe if the measurements made on the MDCT and 3DSS generated models were significantly different from those taken on the dry bones. Additionally, the normality of the data was tested (Shapiro-Wilk test) and the differences in measurements was evaluated using parametric (Student t-tests) and non-parametric (Wilcoxon) tests. The TEM and rTEM calculations show high intra and interobserver consistency in general. However, some measurements present insufficient inter- and intraobserver agreement. Student t and Wilcoxon tests indicate potentially significant differences of some measurements between the different environments. The results show that especially in the virtual environment, it is not easy to find the right angle for some of the DSP measurements, However, when comparing the measurement differences between dry and virtual bones, the results show that most of the differences are less than or equal to 2.5 mm. Considering the IPI, the landmarks are already difficult to determine on the dry bone, but they are even more difficult to locate in the virtual environment. Nevertheless, this study shows that quantitative methods may be better suited for application in the virtual environment, but further research using different methods is needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Five yeast strains isolated from tree bark and rotten wood collected in central and southwestern China, together with four Brazilian strains (three from soil and rotting wood collected in an Amazonian rainforest biome and one from Bromeliad collected in Alagoas state) and one Costa Rican strain isolated from a flower beetle, represent a new species closely related with Yueomyces sinensis in Saccharomycetaceae, as revealed by the 26S ribosomal RNA gene D1/D2 domain and the internal transcribed spacer region sequence analysis. The name Yueomyces silvicola sp. nov. is proposed for this new species with the holotype China General Microbiological Culture Collection Center 2.6469 (= Japan Collection of Microorganisms 34885). The new species exhibits a whole-genome average nucleotide identity value of 77.8% with Y. sinensis. The two Yueomyces species shared unique physiological characteristics of being unable to utilize ammonium and the majority of the amino acids, including glutamate and glutamine, as sole nitrogen sources. Among the 20 amino acids tested, only leucine and tyrosine can be utilized by the Yueomyces species. Genome sequence comparison showed that GAT1, which encodes a GATA family protein participating in transcriptional activation of nitrogen-catabolic genes in Saccharomyces cerevisiae, is absent in the Yueomyces species. However, the failure of the Yueomyces species to utilize ammonium, glutamate, and glutamine, which are generally preferred nitrogen sources for microorganisms, implies that more complicated alterations in the central nitrogen metabolism pathway might occur in the genus Yueomyces., (© 2023 John Wiley & Sons Ltd.)

Understanding what controls global leaf type variation in trees is crucial for comprehending their role in terrestrial ecosystems, including carbon, water and nutrient dynamics. Yet our understanding of the factors influencing forest leaf types remains incomplete, leaving us uncertain about the global proportions of needle-leaved, broadleaved, evergreen and deciduous trees. To address these gaps, we conducted a global, ground-sourced assessment of forest leaf-type variation by integrating forest inventory data with comprehensive leaf form (broadleaf vs needle-leaf) and habit (evergreen vs deciduous) records. We found that global variation in leaf habit is primarily driven by isothermality and soil characteristics, while leaf form is predominantly driven by temperature. Given these relationships, we estimate that 38% of global tree individuals are needle-leaved evergreen, 29% are broadleaved evergreen, 27% are broadleaved deciduous and 5% are needle-leaved deciduous. The aboveground biomass distribution among these tree types is approximately 21% (126.4 Gt), 54% (335.7 Gt), 22% (136.2 Gt) and 3% (18.7 Gt), respectively. We further project that, depending on future emissions pathways, 17-34% of forested areas will experience climate conditions by the end of the century that currently support a different forest type, highlighting the intensification of climatic stress on existing forests. By quantifying the distribution of tree leaf types and their corresponding biomass, and identifying regions where climate change will exert greatest pressure on current leaf types, our results can help improve predictions of future terrestrial ecosystem functioning and carbon cycling., (© 2023. The Author(s).)

Three yeast isolates were obtained from soil and rotting wood samples collected in an Amazonian rainforest biome in Brazil. Comparison of the intergenic spacer 5.8S region and the D1/D2 domains of the large subunit rRNA gene showed that the isolates represent a novel species of the genus Saccharomycopsis . A tree inferred from the D1/D2 sequences placed the novel species near a subclade containing Saccharomycopsis lassenensis , Saccharomycopsis fermentans , Saccharomycopsis javanensis , Saccharomycopsis babjevae , Saccharomycopsis schoenii and Saccharomycopsis oosterbeekiorum , but with low bootstrap support. In terms of sequence divergence, the novel species had the highest identity in the D1/D2 domains with Saccharomycopsis capsularis , from which it differed by 36 substitutions. In contrast, a phylogenomic analysis based on 1061 single-copy orthologs for a smaller set of Saccharomycopsis species whose whole genome sequences are available indicated that the novel species represented by strain UFMG-CM-Y6991 is phylogenetically closer to Saccharomycopsis fodiens and Saccharomycopsis sp. TF2021a (= Saccharomycopsis phalluae ). The novel yeast is homothallic and produces asci with one spheroidal ascospore with an equatorial or subequatorial ledge. The name Saccharomycopsis praedatoria sp. nov. is proposed to accommodate the novel species. The holotype of Saccharomycopsis praedatoria is CBS 16589 T . The MycoBank number is MB849369. S. praedatoria was able to kill cells of Saccharomyces cerevisiae by means of penetration with infection pegs, a trait common to most species of Saccharomycopsis .

In the past two decades, health care has become a global market and transnational practice. An emerging body of literature examines the astounding variety of drivers, conditions, and experiences. However, the question of how traveling abroad for treatment emerges as an option and takes shape in people's illness trajectories has gained little attention thus far. This article attends to this gap by following the stories of people with chronic conditions who travel to India for Ayurveda treatment out of dissatisfaction with local biomedical health care. This study expands the focus of current research on transnational therapeutic mobilities in three ways: (1) by shifting the attention from being a foreign patient or medical traveler to becoming one, (2) by integrating quests for other-than-biomedical therapies, and (3) by applying a narrative approach to the field. Results show that apart from social, human, and financial resources, it takes certain patient-subjectivities to mobilize patients across borders and healing systems., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cranial autonomic dysregulation is a common symptom of patients suffering from cluster headache or migraine. The peripheral vascular dysfunction may increase the risk for ischemic or hemorrhagic strokes, myocardial infarction, retinal vasculopathy, cardiovascular mortality, and peripheral artery diseases. Furthermore, it may also manifest with ocular symptoms, e.g., increased lacrimation, conjunctival injection, and facial swelling., Case Presentation: We here report a case of a patient with migraine and ocular signs of a vascular dysregulation that have led to persisting changes of conjunctival vessels and to a corneal arcus., Conclusions: Autonomic vascular dysregulation may not only cause headaches but also persisting changes of ocular tissues, e.g., conjunctival vessel alterations and a corneal arcus.

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species 1,2 . Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies 3,4 . Here, leveraging global tree databases 5-7 , we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions., (© 2023. The Author(s).)

The increasing resistance to antifungal agents associated with toxicity and interactions turns therapeutic management of fungal infections difficult. This scenario emphasizes the importance of drug repositioning, such as nitroxoline - a urinary antibacterial agent that has shown potential antifungal activity. The aims of this study were to discover the possible therapeutic targets of nitroxoline using an in silico approach, and to determine the in vitro antifungal activity of the drug against the fungal cell wall and cytoplasmic membrane. We explored the biological activity of nitroxoline using PASS, SwissTargetPrediction and Cortellis Drug Discovery Intelligence web tools. After confirmation, the molecule was designed and optimized in HyperChem software. GOLD 2020.1 software was used to predict the interactions between the drug and the target proteins. In vitro investigation evaluated the effect of nitroxoline on the fungal cell wall through sorbitol protection assay. Ergosterol binding assay was carried out to assess the effect of the drug on the cytoplasmic membrane. In silico investigation revealed biological activity with alkane 1-monooxygenase and methionine aminopeptidase enzymes, showing nine and five interactions in the molecular docking, respectively. In vitro results exhibited no effect on the fungal cell wall or cytoplasmic membrane. Finally, nitroxoline has potential as an antifungal agent due to the interaction with alkane 1-monooxygenase and methionine aminopeptidase enzymes, which are not the main human therapeutic targets. These results have potentially revealed a new biological target for the treatment of fungal infections. We also consider that further studies are required to confirm the biological activity of nitroxoline on fungal cells, mainly the confirmation of the alkB gene., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023. Published by Elsevier Masson SAS.)

Phytomedicines such as valerian and St. John's wort are widely used for the treatment of sleeping disorders, anxiety and mild depression. They are perceived as safe alternatives to synthetic drugs, but limited information is available on the intestinal absorption and interaction with human intestinal microbiota of pharmacologically relevant constituents valerenic acid in valerian, and hyperforin and hypericin in St. John's wort. The intestinal permeability of these compounds and the antidepressant and anxiolytic drugs citalopram and diazepam was investigated in the Caco-2 cell model with bidirectional transport experiments. In addition, interaction of compounds and herbal extracts with intestinal microbiota was evaluated in artificial human gut microbiota. Microbiota-mediated metabolisation of compounds was assessed, and bacterial viability and short-chain fatty acids (SCFA) production were measured in the presence of compounds or herbal extracts. Valerenic acid and hyperforin were highly permeable in Caco-2 cell monolayers. Hypericin showed low-to-moderate permeability. An active transport process was potentially involved in the transfer of valerenic acid. Hyperforin and hypericin were mainly transported through passive transcellular diffusion. All compounds were not metabolized over 24 h in the artificial gut microbiota. Microbial SCFA production and bacterial viability was not substantially impaired nor promoted by exposure to the compounds or herbal extracts., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The purpose of this study was to assess the feasibility of detecting relative afferent pupillary defects (RAPDs) using a commercial virtual reality headset equipped with an eye tracker., Methods: This is a cross-sectional study in which we compare the new computerized RAPD test with the traditional clinical standard using the swinging flashlight test. Eighty-two participants including 20 healthy volunteers aged 10 to 88 years were enrolled in this study. We present a bright/dark stimulus alternating between the eyes every 3 seconds using a virtual reality headset, and we simultaneously record changes in pupil size. To determine the presence of an RAPD, we developed an algorithm analyzing the pupil size differences. For the assessment of the performance of the automated and the manual measurement a post hoc impression based on all available data is created. The accuracy of the manual clinical evaluation and the computerized method is compared using confusion matrices and the gold standard of the post hoc impression. The latter is based on all available clinical information., Results: We found that the computerized method detected RAPD with a sensitivity of 90.2% and an accuracy of 84.4%, as compared to the post hoc impression. This was not significantly different from the clinical evaluation with a sensitivity of 89.1% and an accuracy of 88.3%., Conclusions: The presented method offers an accurate, easy to use, and fast method to measure an RAPD. In contrast to today's clinical practice, the measures are quantitative and objective., Translational Relevance: Computerized testing of Relative Afferent Pupillary Defects (RAPD) using a VR-headset and eye-tracking reaches non-inferior performance compared with senior neuro-ophthalmologists.

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L 1 . Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function., (© 2023. The Author(s).)

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 through assembly of extracellular perineuronal nets, which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.

Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and dysfunctional ribosomes degraded both during assembly, as well as the functional cycle. Oxidative stress downregulates translation and damages mRNAs and ribosomal proteins (RPs). Although damaged mRNAs are detected and degraded via RQC, how cells mitigate damage to RPs is not known. Here, we show that cysteines in Rps26 and Rpl10 are readily oxidized, rendering the proteins non-functional. Oxidized Rps26 and Rpl10 are released from ribosomes by their chaperones, Tsr2 and Sqt1, and the damaged ribosomes are subsequently repaired with newly made proteins. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal an unanticipated mechanism for chaperone-mediated ribosome repair, augment our understanding of ribosome quality control, and explain previous observations of protein exchange in ribosomes from dendrites, with broad implications for aging and health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sixteen yeast isolates representing two novel species of the genus Sugiyamaella were obtained from passalid beetles, their galleries and rotting wood collected in three sites of Amazonian Forest in Brazil. Sequence analyses of the ITS-5.8S region and the D1/D2 domains of the large subunit rRNA gene showed that the first species, described here as Sugiyamaella amazoniana f. a., sp. nov. (holotype CBS 18112, MycoBank 847461) is phylogenetically related to S. bonitensis with these species differing by 37 nucleotide substitutions and six gaps in D1/D2 sequences. S. amazoniana is represented by nine isolates obtained from the guts of the passalid beetles Popilius marginatus , Veturius magdalenae , Veturius sinuosus and Spasalus aquinoi , a beetle gallery and rotting wood. The second species, Sugiyamaella bielyi f. a., sp. nov. (holotype CBS 18148, MycoBank 847463), is most phylogenetically related to several undescribed Sugiyamaella species. S. bielyi is described based on seven isolates obtained from the guts of V. magdalenae and V. sinuosus , a beetle gallery and rotting wood. Both species appear to be associated with passalid beetles and their ecological niches in Amazonian biome.

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John's wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John's wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin - but not to valerenic acid - is likely to be minimal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Spiess, Abegg, Chauveau, Rath, Treyer, Reinehr, Kuoni, Oufir, Potterat, Hamburger and Simões-Wüst.)

Studying species interactions in nature often requires elaborated logistics and intense fieldwork. The difficulties in such task might hinder our ability to answer questions on how biotic interactions change with the environment. Fortunately, a workaround to this problem lies within scientific collections. For some animals, the inspection of preserved specimens can reveal the scars of past antagonistic encounters, such as predation attempts. A common defensive behaviour that leaves scars on animals is autotomy, the loss of a body appendage to escape predation. By knowing the collection site of preserved specimens, it is possible to assess the influence of organismal biology and the surrounding environment in the occurrence of autotomy. We gathered data on tail loss for 8189 preserved specimens of 33 snake and 11 amphisbaenian species to investigate biological and environmental correlates of autotomy in reptiles. We applied generalized linear mixed effect models to evaluate whether body size, sex, life-stage, habitat use, activity pattern, biome, tropicality, temperature and precipitation affect the probability of tail loss in limbless reptiles. We observed autotomy in 23.6% of examined specimens, with 18.7% of amphisbaenian and 33.4% of snake specimens showing tail loss. The probability of tail loss did not differ between snakes and amphisbaenians, but it was higher among large-sized specimens, particularly in adults and females. Chance of tail loss was higher for diurnal and arboreal species, and among specimens collected in warmer regions, but it was unaffected by biome, precipitation, and tropicality. Autotomy in limbless reptiles was affected by size-dependent factors that interplay with ontogeny and sexual dimorphism, although size-independent effects of life-stage and sex also shaped behavioural responses to predators. The increase in probability of tail loss with verticality and diurnality suggests a risk-balance mechanism between species habitat use and activity pattern. Although autotomy is more likely in warmer regions, it seems unrelated to seasonal differences in snakes and amphisbaenians activity. Our findings reveal several processes related to predator-prey interactions involving limbless reptiles, demonstrating the importance of scientific collections to unveil ecological mechanisms at different spatio-temporal scales., (© 2022 The Authors. Journal of Animal Ecology © 2022 British Ecological Society.)

The placental passage of protopine was investigated with a human ex vivo placental perfusion model. The model was first validated with diazepam and citalopram, 2 compounds known to cross the placental barrier, and antipyrine as a positive control. All compounds were quantified by partially validated U(H)PLC-MS/MS bioanalytical methods. Protopine was transferred from the maternal to the fetal circuit, with a steady-state reached after 90 min. The study compound did not affect placental viability or functionality, as glucose consumption, lactate production, and beta-human chorionic gonadotropin, and leptin release remained constant. Histopathological evaluation of all placental specimens showed unremarkable, age-appropriate parenchymal maturation with no pathologic findings., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

This study investigated the diversity of yeast species associated with rotting wood in Brazilian Amazonian rainforests. A total of 569 yeast strains were isolated from rotting wood samples collected in three Amazonian areas (Universidade Federal do Amazonas-Universidade Federal do Amazonas [UFAM], Piquiá, and Carú) in the municipality of Itacoatiara, Amazon state. The samples were cultured in yeast nitrogen base (YNB)-d-xylose, YNB-xylan, and sugarcane bagasse and corncob hemicellulosic hydrolysates (undiluted and diluted 1:2 and 1:5). Sugiyamaella was the most prevalent genus identified in this work, followed by Kazachstania. The most frequently isolated yeast species were Schwanniomyces polymorphus, Scheffersomyces amazonensis, and Wickerhamomyces sp., respectively. The alpha diversity analyses showed that the dryland forest of UFAM was the most diverse area, while the floodplain forest of Carú was the least. Additionally, the difference in diversity between UFAM and Carú was the highest among the comparisons. Thirty candidates for new yeast species were obtained, representing 36% of the species identified and totaling 101 isolates. Among them were species belonging to the clades Spathaspora, Scheffersomyces, and Sugiyamaella, which are recognized as genera with natural xylose-fermenting yeasts that are often studied for biotechnological and ecological purposes. The results of this work showed that rotting wood collected from the Amazonian rainforest is a tremendous source of diverse yeasts, including candidates for new species., (© 2022 John Wiley & Sons Ltd.)

The cepafungins are a class of highly potent and selective eukaryotic proteasome inhibitor natural products with potential to treat refractory multiple myeloma and other cancers. The structure-activity relationship of the cepafungins is not fully understood. This Article chronicles the development of a chemoenzymatic approach to cepafungin I. A failed initial route involving derivatization of pipecolic acid prompted us to examine the biosynthetic pathway for the production of 4-hydroxylysine, which culminated in the development of a 9-step synthesis of cepafungin I. An alkyne-tagged analogue enabled chemoproteomic studies of cepafungin and comparison of its effects on global protein expression in human multiple myeloma cells to the clinical drug bortezomib. A preliminary series of analogues elucidated critical determinants of potency in proteasome inhibition. Herein we report the chemoenzymatic syntheses of 13 additional analogues of cepafungin I guided by a proteasome-bound crystal structure, 5 of which are more potent than the natural product. The lead analogue was found to have 7-fold greater proteasome β5 subunit inhibitory activity and has been evaluated against several multiple myeloma and mantle cell lymphoma cell lines in comparison to the clinical drug bortezomib., Competing Interests: The authors declare the following competing financial interest(s): A. Amatuni, A. Shuster, A. Adibekian, and H. Renata have applied for a provisional patent for this work., (© 2023 The Authors. Published by American Chemical Society.)

Previous attempts to quantify tree abundance at global scale have largely neglected the role of local competition in modulating the influence of climate and soils on tree density. Here, we evaluated whether mean tree size in the world's natural forests alters the effect of global productivity on tree density. In doing so, we gathered a vast set of forest inventories including >3000 sampling plots from 23 well-conserved areas worldwide to encompass (as much as possible) the main forest biomes on Earth. We evidence that latitudinal productivity patterns of tree density become evident as large trees become dominant. Global estimates of tree abundance should, therefore, consider dependencies of latitudinal sources of variability on local biotic influences to avoid underestimating the number of trees on Earth and to properly evaluate the functional and social consequences., (© 2023. The Author(s).)

Background/aims: The aim of this study was to identify specific MRI characteristics of anterior ischaemic optic neuropathy (AION) and optic neuritis (ON) that would aid in the differentiation between these two diagnoses., Methods: We retrospectively analysed a consecutive case series including all patients with an MRI study of brain and orbit and the clinical diagnosis of either ON or AION. We examined the scans for restricted diffusion of the optic nerve, optic sheath diameter, enhancement and location of enhancement of the optic nerve and distribution of the white matter lesions., Results: Fifty patients met the inclusion criteria. We found an accuracy of 0.98 for the discrimination between AION and ON based solely on parameters extracted from MRI data. Dominance analysis to determine the most influential parameters showed that the enhancement pattern of the optic nerve and distribution of the white matter lesions had the biggest impact on the classification and led to a discrimination accuracy of 0.9 when used alone., Conclusion: In patients with an inconclusive clinical diagnosis, optic nerve enhancement pattern and distribution of white matter lesions can aid in the diagnosis and differentiation between AION and ON. Diffusion-weighted imaging did not add significant information to the diagnosis or help to differentiate between the two conditions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Rational Emotive Behavior Therapy's (REBT's) ABC model proposes that it is B, Beliefs about A, Activating events, not A, Activating events themselves, that create and control C, emotional Consequences. Codified beliefs such as scriptures and creeds are prominent in most religions. Integrating codified religious beliefs with REBT to help D, Dispute irrational beliefs has been studied in REBT for more than 50 years. Broad knowledge of religious cultures, scriptures, creeds, and wisdom literature is likely to help REBTers and other cognitive behavior therapists (CBTers) more effectively treat religious clients. We give a brief overview of the history, culture, doctrine, and scriptures of the Church of Jesus Christ of Latter-day Saints, then give examples of REBT Disputations excerpted from religion integrative sessions with practicing Latter-day Saint clients. We present practice-based evidence for the effectiveness of this approach and offer suggestions for future study and research in integrating religion with REBT and CBT., Competing Interests: Conflict of interestThe authors declare that they have no conflicts of interest., (© The Author(s) 2023.)

Background: Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (MS ped ) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD ped ) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode., Methods: Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls., Results: Thirteen MOGAD ped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 MS ped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in MOGAD ped compared to MS ped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p < 0.001; mRNFL: 0.12 ± 0.01 vs. 0.14 ± 0.01 mm 3 , p < 0.001). Neither other macular layers nor P100 latency differed. MOGAD ped developed global atrophy affecting all peripapillary segments, while MS ped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff < 62.5 µm, 90.5% sensitivity and 70.8% specificity for MOGAD ped ). OCT was also substantially more sensitive compared to VEP in identification of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016)., Conclusion: First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON., (© 2022. The Author(s).)

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups., Competing Interests: Declaration of interests AP received grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medical Centre, Department of Neurology, MS Centre (RESTORE trial), and UCL, London RECOVER trial; received grant fees from Fight for Sight (nimodipine in optic neuritis trial); received royalties or licenses from Up-to-Date (Wolters Kluwer) for a book chapter; received speaker fees for the Heidelberg Academy; participates on advisory board for SC Zeiss OCTA Angi-Network, and the SC Novartis OCTiMS study; holds leadership roles for governing board IMSVISUAL; was chairman of ERN-EYE Neuro-ophthalmology (until Oct, 2020); is board member of National Dutch Neuro-ophthalmology Association; received equipment from OCTA from Zeiss (Plex Elite); and received medical writing support from Novartis for a manuscript (https://doi.org/10.1002/acn3.51473). CF received consulting fees from Invex Therapeutics; received speaker honoraria from University of Dunedin; and holds leadership as Director of Royal Australian and New Zealand College of Ophthalmologists. VB received personal fees as consultant for Gensight and Neurophoenix. PC obtained grants from Annexon, Biogen, Genentech; received royalties from Cambridge Press for an OCT book; received consulting fees from Disarm Therapeutics, Nervgen, Biogen, Avidea; received honoraria from NY Academy of Sciences; and received equipment from Myelin Repair Foundation, Academic CME, Neuraly, and Landos. FC received speaker honoraria from Alexion, Accure Therapeutics, and the Sumiara Foundation. RDe obtained consulting fees from Alexion. JdS received consulting fees from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, CSL Behring; and honoraria from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, and CSL Behring. JFR received consulting fees from Roche, and Sanofi. EF holds honoraria from Alexion, Genzyme, Biogen, Novartis, and Janssen. TF holds honoraria from Alexion. CFT received honoraria from Novartis; and received support for attending meetings and travel from Novartis and Teva. KF obtained grants from Ministry of Education, Science and Technology of Japan as well as the Ministry of Health, Welfare and Labor of Japan; received consulting fees from Alexion Chugai-Roche Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Teijin, Viela Bio, UCB, Merck, Japan Tobacco Pharma, and Abbvie; received honoraria from Alexion, Chugai-Roche, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, and Bayer; participated on a data safety monitoring board or advisory board from Alexion, Chugai, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, UCB, and Viela Bio; and received medical writing support from Oxford PharmaGenesis and Apothecom. RG acquired personal fees for participation on data safety monitoring boards, and served on the advisory boards for Biogen, Hikma, Merck, Roche, and Sanofi as well as receiving a grant from Roche. FG received grants or contracts from Roche (NMO epidemiologic studies) and Novartis (MS epidemiologic studies); received honoraria from for lectures from Roche, Novartis, Stendhal, and Merck; received support for attending meetings from the European Charcot Foundation, and ECTRIMS; and reports leadership of FOCEM (Foro Centroamericano y del Caribe de la Esclerosis Múltiple y otras enfermedades desmielinizantes del Sistema Nervioso Central) and Academia Panameña de Medicina y Cirugía (both unpaid). MHab obtained honoraria from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, Roche, and Zentiva; received support for attending meetings from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche; and participated on advisory board for Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche. ZIl obtained grants or contracts from Biogen and Alexion; received honoraria from Biogen, Novartis, Roche, Merck, and Alexion; received payment for expert testimony from Roche; received support for attending meetings and travel from Biogen and Sanofi; and participated on a data safety monitoring board or advisory board from Biogen, Novartis, Merck, Sanofi, Roche, and Alexion. HJK received grants or contracts from National Research Foundation of Korea, Aprilbio, and Eisai; received consulting fees from Aprilbio, Daewoong, HanAll BioPharma, MDimune, Roche, Sanofi Genzyme, Teva-Handok, UCB, and Viela Bio; and received honoraria from Alexion, Biogen, Celltrion, Eisai, GC Pharma, Merck Serono, Novartis, Sanofi Genzyme, and Teva-Handok. RM received consulting fees from UCB, Alexion, Merck, Viela Bio, Novartis, and Roche; and participated on an advisory board for Viela Bio and Roche. FP obtained research support from Alexion; received grants or contracts from German Ministry for Research Support Recipient Charité Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck, Serono, Novartis, Bayer, Roche, Parexel, and Almirall; received honoraria from the Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; received support for attending meetings from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; participated on an advisory board for Celgene, Roche, UCB, Merck; and reports leadership as academic editor for Plos One, and associate editor for Neurology, Neuroimmunology, and Neuroinflammation. MBR received support for attending meeting from Novartis. BSD received consulting fees from Chiesi; received honoraria from Chiesi and Sanofi; received support for attending meetings from Bausch + Lomb; participated on an advisory board for Chiesi; and has stock options from Accure Therapeutics. DS received grants or contracts from National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), American Academy of Neurology (AAN), National Institute of Aging (NIA), National Multiple Sclerosis Society (NMSS), and United States Department of State; and was a committee member for Multiple Sclerosis International Federation (MSIF) and American Neurological Association (ANA). AS received grants or contracts from the Turkish MS society, and Istanbul University Research Support Grants; received consulting fees from Roche, Merck Serono, Biogen, Gen Pharma of Türkiye, Sanofi Genzyme, and Novartis; received honoraria from Sanofi Genzyme, Novartis, Roche, and Teva; and received support for attending meetings from Sanofi Genzyme. VvP obtained grants or contracts from Biogen; received consulting fees from Biogen, Merck, Sanofi, BMS, Novartis, Janssen, Almirall, and Roche; received honoraria from Biogen, Merck, Sanofi, BMS, Novartis, Roche; and received support for attending meetings from Biogen, Roche, and Almirall. MPW received royalties from Springer Healthcare and Elsevier; received consulting fees from Biogen, Roche, Biologix, Novartis, BMS-Celgene, Imcyse, Merck Serono, Sanofi Aventis, IXICO, and Icometrix; received honoraria from Bayer, Biogen, Biologix, Genilac, Novartis, Medison, Merck Serono, Roche, Sanofi Aventis, and BMS-Celgene; and participated on a data safety monitoring board for VU University Medical Center. LB received consulting fees as editor for the Journal of Neuro-Ophthalmology. GTP is an Emeritus editor for Neuro-ophthalmology. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ribonuclease targeting chimeras (RiboTACs) induce degradation of an RNA target by facilitating an interaction between an RNA and a ribonuclease (RNase). We describe the screening of a DNA-encoded library (DEL) to identify binders of monomeric RNase L to provide a compound that induced dimerization of RNase L, activating its ribonuclease activity. This compound was incorporated into the design of a next-generation RiboTAC that targeted the microRNA-21 (miR-21) precursor and alleviated a miR-21-associated cellular phenotype in triple-negative breast cancer cells. The RNA-binding module in the RiboTAC is Dovitinib, a known receptor tyrosine kinase (RTK) inhibitor, which was previously identified to bind miR-21 as an off-target. Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.

Background: High-resolution optical coherence tomography (OCT) allows the detection of macular pathology and involvement of the optic nerve in a wide spectrum of diseases. For the differentiation of diseased and healthy status, normal values of retinal layer segmentation are critical. Yet, normative values mostly cover adult populations with only sparse data for paediatric cohorts. We present data of retinal layer characteristics via OCT in a healthy paediatric cohort., Methods: This prospective cross-sectional study screened 75 healthy children (male = 42, female = 33, range 4-17 years) without visual problems. OCT was performed with a peripapillary ring and macula scan protocol to determine paediatric normative values for routine parameters (peripapillary retinal nerve fibre layer thickness (pRNFL), total macular volume (TMV), macular retinal thickness (RT)). The macula scan (6mm grid) was segmented using the device-inherent automated segmentation software (Heidelberg Eye Explorer) for retinal layers: RNFL, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) in 9 segments each and mean of the 9 segments., Results: We obtained OCT data of 72 children with mean age 12.49 years (standard deviation, SD, 2.18; minimum 3.93). Mean global pRNFL was 102.20 μm (SD 8.24), mean TMV 8.81 mm3 (0.30) and mean RT (all segments) 318.22 μm (10.19). Segmented macular retinal layer thicknesses (mean of all segments) were: RNFL 27.67 μm (2.14), GCL 41.94 μm (2.50), IPL 34.97 μm (2.10), INL 35.18 μm (2.15), OPL 29.06 μm (2.24), ONL 68.35 μm (6.20)., Conclusion: The OCT is a useful non-invasive imaging technique for the examination of the retina in children with short duration, high imaging resolution and no known adverse effects. Normative values may serve as a comparator for different neuropaediatric disorders and are first presented with this study using an up-to-date and standardized OCT imaging technique., Competing Interests: RG has received speaker and board honoraria from Baxter, Bayer Schering, Biogen Idec, Bristol Meyer Squibb, CSL Behring, Eisai, Genzyme, Janssen, Merck Serono, Novartis, Stendhal, Talecris and TEVA. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis and TEVA. All of RG’s declarations are unrelated to the content of this manuscript. AS has received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, Novartis, and Roche, and research support by the Swiss MS Society and Baasch Medicus Foundation, not related to this manuscript. AKR, MA, JR, TF, DB, KWU, TL, RG, AS have no competing interests to declare that are relevant to the content of this article.

The latitudinal diversity gradient (LDG) is one of the most recognized global patterns of species richness exhibited across a wide range of taxa. Numerous hypotheses have been proposed in the past two centuries to explain LDG, but rigorous tests of the drivers of LDGs have been limited by a lack of high-quality global species richness data. Here we produce a high-resolution (0.025° × 0.025°) map of local tree species richness using a global forest inventory database with individual tree information and local biophysical characteristics from ~1.3 million sample plots. We then quantify drivers of local tree species richness patterns across latitudes. Generally, annual mean temperature was a dominant predictor of tree species richness, which is most consistent with the metabolic theory of biodiversity (MTB). However, MTB underestimated LDG in the tropics, where high species richness was also moderated by topographic, soil and anthropogenic factors operating at local scales. Given that local landscape variables operate synergistically with bioclimatic factors in shaping the global LDG pattern, we suggest that MTB be extended to account for co-limitation by subordinate drivers., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)