Explore the vast range of titles available.

Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. Syndromic as well as nonsyndromic forms of ichthyosis exist. Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. In nonsyndromic forms, these features are most evident in severe autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis, but to some extent also occur in the common type of non-congenital ichthyosis. A correct diagnosis of ichthyosis—essential not only for genetic counseling but also for adequate patient information about prognosis and therapeutic options—is becoming increasingly feasible thanks to recent progress in genetic knowledge and DNA sequencing methods. This paper reviews the most important aspects of nonsyndromic ichthyoses, focusing on new knowledge about the pathophysiology of the disorders, which will hopefully lead to novel ideas about therapy.

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4 + and CD8 + T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD. Graphical Abstract

Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock‐in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV‐based strategy carrying intein‐split‐dCas9 in combination with activators (AAV‐dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single‐cell transcriptome analysis of reprogrammed neurons in vivo . These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6‐OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV‐dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease. Synopsis GABAergic neurons generated by CRISPR‐mediated direct reprogramming of striatal astrocytes rescue voluntary motor behavior in a toxin‐induced murine model for Parkinson's disease, suggesting a novel intervention strategy beyond the restoration of dopamine levels. A novel CRISPRa mouse line dCAM is developed for the conditional induction of endogenous target genes. An AAV‐based split‐dCas9‐activator system is established for translational applications of CRISPRa. Direct reprogramming of murine striatal astrocytes using the factor combination Ascl1 , Lmx1a , and Nr4a2 results in induced GABAergic neurons in vivo . Induced GABAergic neurons are capable of ameliorating specific motor symptoms of Parkinson's disease. Graphical Abstract GABAergic neurons generated by CRISPR‐mediated direct reprogramming of striatal astrocytes rescue voluntary motor behavior in a toxin‐induced murine model for Parkinson's disease, suggesting a novel intervention strategy beyond the restoration of dopamine levels.

Sulfoquinovosyldiacylglycerol (SQDG) is a glycolipid ubiquitously found in photosynthetically active organisms. It has attracted much attention in recent years due to its biological activities. Similarly, the increasing demand for vegan and functional foods has led to a growing interest in micronutrients such as sulfolipids and their physiological influence on human health. To study this influence, reference materials are needed for developing new analytical methods and providing enough material for model studies on the biological activity. However, the availability of these materials is limited by the difficulty to isolate and purify sulfolipids from natural sources and the unavailability of chemical standards on the market. Consequently, an alternative synthetic route for the comprehensive preparation of sulfolipids was established. Here, the synthesis of a sulfolipid with two identical saturated fatty acids is described exemplarily. The method opens possibilities for the preparation of a diverse range of interesting derivatives with different saturated and unsaturated fatty acids.

Losses of suitable foraging and nesting habitats are key drivers for ongoing declines of farmland birds. For Eurasian Skylarks (Alauda arvensis), this is reflected by the lack of sparse and short vegetation structure (i.e., crop architecture). Existing countermeasures outside cultivated areas seem unable to offset declines, indicating the need for in‐field measures, ideally in cereal fields which cover large shares of agricultural land and ideally without compromising yields. We experimentally tested whether unsown Skylark strips in intensive winter cereal fields (treatment) provided sparse and short crop architecture throughout the breeding season and whether this improved habitat quality by comparing key parameters of Skylark populations on treatment fields and fields without Skylark strips (control). Further, we tested whether the size and direction of effects of the measure depended on surrounding landscape features and seasonality. Breeding performance was improved in treatment fields: the odds for nests being successful were 12.5 times that of control fields. During important phases of the breeding season, prey density and parental foraging were increased in treatment fields. Territorial behavior was higher in treatment fields throughout the breeding season, which was also less dependent on other attractants (i.e., proximity to ecotones) compared to control fields. Habitat use was increasingly higher in treatment fields as the breeding season progressed. Further, the availability of small‐parceled fields in the surrounding area was related to decreased habitat use in control fields but not in treatment fields. In general, habitat use in cereal fields depended on adjacent habitat types, with the presence of spring sown crops leading to the largest declines. We conclude that Skylark strips can improve habitat quality for Skylark nesting and foraging in intensive winter cereal fields. Given the previously shown yield stability, this encourages large‐scale implementation of this measure for Skylark conservation, which might be most beneficial on large winter cereal fields in landscapes where there are few spring‐sown crops. Eurasian Skylarks decline is attributed to loss of suitable nesting and foraging habitats, highlighting the need for mitigating in‐field measures. The study found that unsown Skylark strips in intensive winter cereal fields improved habitat quality for Skylarks in terms of breeding performance, prey density, parental foraging patterns, territorial behavior, and habitat use. This suggests that large‐scale implementation of Skylark strips may be effective for Skylark conservation, with analysis of landscape features showing that the effects may be greatest in large winter cereal fields in landscapes where there are few spring‐sown crops.

Pityriasis rubra pilaris is a rare inflammatory papulosquamous skin disease without any approved treatment options. Variants in the CARD14 (caspase recruitment domain family member 14) gene have been identified to play a role in the pathophysiology of atypical juvenile PRP by activating the IL-23/IL-17A cytokine axis, highlighting this pathway as a potential target of therapy. Here, we present a case of successful treatment with ixekizumab, a humanized monoclonal anti-IL-17A antibody, in an atypical juvenile PRP (type V) patient with a novel variant of CARD14 mutation.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson's disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human [alpha]-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4.sup.+ and CD8.sup.+ T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of [alpha]-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an [alpha]-synuclein mouse model for progressive PD.

Astrocyte heterogeneity has been well explored, but our understanding of white matter (WM) astrocytes and their distinctions from gray matter (GM) astrocytes remains limited. Here, we compared astrocytes from cortical GM and WM/corpus callosum (WM/CC) using single-cell RNA sequencing and spatial transcriptomics of the murine forebrain. The comparison revealed similarities but also significant differences between WM and GM astrocytes, including cytoskeletal and metabolic hallmarks specific to WM astrocytes with molecular properties also shared with human WM astrocytes. When we compared murine astrocytes from two different WM regions, the cortex and cerebellum, we found that they exhibited distinct, region-specific molecular properties, with the cerebellum lacking, for example, a specific cluster of WM astrocytes expressing progenitor and proliferation genes. Functional experiments confirmed astrocyte proliferation in the WM/CC, but not in the cerebellar WM, suggesting that the WM/CC may be a source of continued astrogenesis. White matter (WM) astrocytes differ significantly from gray matter astrocytes, with WM astrocytes in the forebrain exhibiting unique proliferation capacity, which is absent in cerebellar WM, suggesting region-specific astrocyte generation.

Recent progress in the genetics of autosomal recessive congenital ichthyosis (ARCI) has illustrated the power of genetic strategies for the investigation of newly recognized metabolic pathways and for the mechanisms of barrier function in normal skin. Parallel biochemical studies have elucidated important functional aspects of these findings (Brash et al., 2007), and it is now time to determine how the genetic and biochemical features correlate with the clinical phenotypes of patients. The story of ARCI provides an instructive example of synergy among geneticists, biochemists, and clinicians.