Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutationsabhängige Mechanismen und deren Bedeutung für zielgerichtete Behandlungsstrategien am Beispiel von Bestrophin 1 und den Bestrophinopathien

Zusammenfassung Das Bestrophin-1-Gen (BEST1) codiert für ein integrales Membranprotein und findet sich im basolateralen Aspekt des retinalen Pigmentepithels. Mutationen im BEST1 sind mit einer heterogenen Gruppe von erblichen Netzhautdystrophien assoziiert, den sog. Bestrophinopathien, die schon in jüngerem Alter zu einer Beeinträchtigung des Sehvermögens führen können. Die einzelnen Krankheitsbilder sind anhand ihrer phänotypischen Merkmale und Erbgänge abgrenzbar. Während die meisten BEST1-Mutationen einem autosomal-dominanten Erbgang folgen, bei dem bereits eine defekte Genkopie zur Erkrankung führt, sind bei der autosomal-rezessiven Bestrophinopathie heterozygote Mutationsträger i. d. R. symptomfrei. In diesem Übersichtsartikel soll am Beispiel der Bestrophinopathien die Bedeutung der Kenntnis von mutationsabhängigen Mechanismen für das Verständnis der Pathogenese, aber auch für die Entwicklung von zukünftigen Therapieansätzen, hervorgehoben werden.
Cannabis and Cognition: Connecting the Dots towards the Understanding of the Relationship

Several studies have advanced the understanding of the effects of cannabis on cognitive function. A comprehensive reappraisal of such literature may help in drawing conclusions about the potential risks associated with cannabis use. In summary, the evidence suggests that earlier age of use, high-frequency and high-potency cannabis use, as well as sustained use over time and use of synthetic cannabinoids, are all correlated with a higher likelihood of developing potentially severe and persistent executive function impairments. While the exact mechanisms underlying the adverse effects of cannabis on cognition are not completely clear, Magnetic Resonance Imaging (MRI) studies support the presence of both structural and functional alterations associated with cannabis use. Cognitive dysfunction is also a core feature of many neuropsychiatric disorders and care must be taken regarding the effects of cannabis use in these patient populations. Cognitive impairments affect patients’ daily functions, sociability, and long-term outcome, posing elevated economic, social, and clinical burdens. There is, thus, a compelling case for implementing behavioral and cognitive rehabilitation therapies for these patients, as well as investigating the endocannabinoid system in the development of new psychopharmacological treatments.
Analysis of expression of p63 and caspase-3 and their predictive value in patients with squamous cell carcinoma of maxillary sinus.

OBJECTIVE Introduction: Maxillary sinus cancer is a malignant neoplasm with a prevalence of 3 to 5% of tumors in the head and neck and less than 1% of all malignant neoplasms. The role of p63 and caspase-3 and their predictive value in squamous cell carcinoma of maxillary sinus (SCCMS) remains an underdeveloped and controversial issue that determined the relevance of the study. The aim: To analyze the relationship between the level of expression of p63 and caspase-3 and clinical and morphological characteristics of squamous cell carcinoma of maxillary sinus and to determine their prognostic significance as immunohistochemical markers of tumor progression (relapse and metastases). PATIENTS AND METHODS Materials and methods: A comprehensive investigation with immunohistochemical study of squamous cell carcinoma of maxillary sinus of 103 patients with maxillary sinus cancer II - IV stage (T2-4 N0-3 M0) of the second clinical group was conducted. RESULTS Results: The moderate and high expression rate of caspase-3 in the overall sample was 50.49% and 16.50% respectively, and one third of cases (33.01%) was characterized by a weak reaction. In the group without metastases (p <0.001), moderate expression of the marker (56.25%) prevailed; in the SCCMS group with metastases it was (60.87%). The mean level of expression of p63 in the examined patients with squamous cell carcinoma of maxillary sinus was 46.0%. The number of p63-positive specimens was statistically significantly (p = 0.034) higher in the SCCMS group with metastases. In patients with the development of squamous cell carcinoma of maxilla on the background of papilloma, a significantly higher (p <0.001) mean level of p63 expression was only moderate (90.91%) and high (9.09%). CONCLUSION Conclusions: There was observed a relatively strong associate of the increase in the expression of caspase-3 with SCCMS metastases (p <0.001) and no correlation of immunohistochemical reaction of this marker with relapses. There was determined that the probability of metastases at high expression level of p63 is higher than in tumors with low and moderate level of the oncoprotein (p = 0.003). Based on the level of expression of p63, it is possible to predict the likelihood of development of SCCMS with papillomas (p <0.001); and the development of relapses of squamous cell carcinoma of maxillary sinus (p <0.001).
Prespecified Four Kallikrein Marker Model (4Kscore) at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population-Based Cohort of Asymptomatic Men Followed for 20 Years.

PURPOSE A pre-specified statistical model based on four kallikrein markers in blood, commercially available as the 4Kscore, has been shown to accurately detect high grade (>Grade Group 2) prostate cancer in men with moderately elevated PSA. We aimed to assess whether the model predicted prostate cancer metastasis or death in men not subject to PSA screening. MATERIALS AND METHODS The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population-based cohort with low rates of PSA screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 from men in this cohort, we analyzed the association between PSA and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death. RESULTS There were 308 with metastases, and 172 prostate cancer deaths. Baseline PSA was strongly associated with 20-year risk of prostate cancer death (c-index at age 50: 0.859, 95% CI 0.799-0.916; age 60: 0.840, 95% CI 0.799-0.878). Men aged 60 with PSA below median (<1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated PSA (≥2.0 ng/ml), the 4Kscore markedly improved discrimination (c-index 0.767 vs. 0.828 and 0.774 vs. 0.862 in men 50 and 60). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low. CONCLUSION Screening should focus on men in top PSA-quartile at age 60. Men with elevated PSA but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.
Spatiotemporal Profile and Morphological Changes of NG2 Glia in the CA1 Region of the Rat Hippocampus after Transient Forebrain Ischemia

Neuron-glial antigen-2 (NG2) glia undergo proliferation and morphological changes following brain insults. Here, we show that NG2 glia is activated in a characteristic time- and layer-specific manner in the ischemia-vulnerable CA1 region of the rat hippocampus. Resting NG2 glia of the pyramidal cell layer (somatic region) shared morphological features with those of the neighboring dendritic stratum radiatum. During the postischemic period, reactive NG2 glia of the pyramidal cell layer exhibited shortened, scarcely branched processes, while those of the stratum radiatum had multiple branching processes with their arborization being almost indiscernible 7~14 days after reperfusion. Immunoelectron microscopy demonstrated that NG2 immunoreactivity was specifically associated with the plasma membrane and the adjacent extracellular matrix of NG2 glia in the stratum radiatum at 14 days. NG2 glia also exhibited differences in their numbers and proliferation profiles in the two examined hippocampal strata after ischemia. In addition, induced NG2 expression in activated microglia/macrophages exhibited a characteristic strata-dependent pattern in the ischemic CA1 hippocampus. NG2 induction was prominent in macrophage-like phenotypes which were predominantly localized in the pyramidal cell layer, compared with activated stellate microglial cells in the stratum radiatum. Thus, our data demonstrate that activation of NG2 glia and the induction of NG2 expression in activated microglia/macrophages occur in a distinct time- and layer-specific manner in the ischemic CA1 hippocampus. These characteristic profiles of reactive NG2 glia could be secondary to the degeneration processes occurring in the cell bodies or dendritic domains of hippocampal CA1 pyramidal neurons after ischemic insults.
A Synthetic Approach Allows Rapid Characterization of the Maize Nuclear Auxin Response Circuit1[OPEN]

A synthetic maize auxin response circuit recapitulated in Saccharomyces cerevisiae reveals an auxin signaling network with functional homology to the Arabidopsis circuit. Auxin plays a key role across all land plants in growth and developmental processes. Although auxin signaling function has diverged and expanded, differences in the molecular functions of signaling components have largely been characterized in Arabidopsis (Arabidopsis thaliana). Here, we used the nuclear Auxin Response Circuit recapitulated in yeast (Saccharomyces cerevisiae) system to functionally annotate maize (Zea mays) auxin signaling components, focusing on genes expressed during the development of ear and tassel inflorescences. All 16 maize auxin/indole-3-acetic acid repressor proteins were degraded in response to auxin with rates that depended on both receptor and repressor identities. When fused to the maize TOPLESS homolog RAMOSA1 ENHANCER LOCUS2, maize auxin/indole-3-acetic acids were able to repress AUXIN RESPONSE FACTOR transcriptional activity. A complete auxin response circuit comprising all maize components, including the ZmAFB2/3 b1 maize AUXIN SIGNALING F-BOX (AFB) receptor, was fully functional. The ZmAFB2/3 b1 auxin receptor was more sensitive to hormone than AtAFB2 and allowed for rapid circuit activation upon auxin addition. These results validate the conserved role of predicted auxin response genes in maize as well as provide evidence that a synthetic approach can facilitate broader comparative studies across the wide range of species with sequenced genomes.
Implications of Hemostasis Disorders in Patients with Critical Limb Ischemia—An In-Depth Comparison of Selected Factors

Background: Atherosclerosis is a systemic disease. Among patients with atherosclerosis, those suffering from peripheral arterial disease (PAD) represent a group of individuals with particularly high death risk, especially during the course of critical limb ischemia (CLI). In the pathogenesis of PAD/CLI complications, blood coagulation disorders play a significant role. The study aim was to examine the activation of the coagulation system depending on tissue factor (TF) in patients with CLI as compared with those with intermittent claudication (IC). Methods: Before initiating proper treatment (invasive or maintenance), blood samples were collected from 65 patients with CLI and 15 with IC to measure the following selected hemostasis parameters: concentrations and activation of tissue factor (TF Ag and TF Act) and tissue factor pathway inhibitor (TFPI Ag and TFPI Act), concentrations of thrombin–antithrombin complex (TAT Ag) and fibrinogen, platelet count (PLT), and concentrations of tissue-plasminogen activator (t-PA Ag), plasminogen activator inhibitor 1 (PAI-1), and D-dimer. The control group included 30 healthy volunteers (10 female/20 male). Results: The values of all analyzed parameters (except for lower TFPI Act) were significantly higher in the blood of PAD patients (with respect to PLT only in the CLI subgroup) in comparison with healthy subjects. The blood of patients with CLI as compared to the IC subgroup revealed much higher concentrations of TF Ag (p < 0.001), with slightly decreased TF Act, significantly lower concentrations of TFPI Ag (p < 0.001), slightly increased TFPI Act, and significantly higher levels of TAT Ag (p < 0.001), fibrinogen (p = 0.026), and D-dimer (p < 0.05). Conclusions: In patients with CLI, we can observe coagulation activation and a shifting balance toward prothrombotic processes. Furthermore, increased concentrations of D-dimer suggest a secondary activation of fibrinolysis and confirm the phenomenon as a prothrombotic condition with heightened fibrinolysis.
Use of Diagnostic Injections to Evaluate Sacroiliac Joint Pain

ABSTRACT The sacroiliac joint is a complex, variable, and irregular structure, thought to be the source of 15% to 30% of low back, pelvic, and radicular pain. Several predisposing factors, including prior spinal surgery and particularly lumbar fusion, can contribute to joint inflammation and acceleration of joint degeneration. Evaluation of the sacroiliac joint as a pain generator using history and physical alone can prove difficult, because a number of other pathologies can have a similar presentation. Whereas a number of tests are used to examine the joint, no single test alone has proven validity. Imaging alone has also not been proven efficacious, particularly in nonspondyloarthropathy-mediated pain. Although no “gold standard” exists, diagnostic sacroiliac joint block has been shown to be a useful confirmatory tool in assessing sacroiliac (SI) joint–mediated pain. Sacroiliac joint injection with local anesthetic and steroids can be used as a possible therapeutic endeavor to manage pain and inflammation.
The effect of hydrochloric acid (HCl) on permanent molars: A scanning electron microscope (SEM) and energy dispersive X-ray spectroscopy (EDS) study

It is well established that acid disposal is a potentially effective method used by criminal syndicates to hinder the identification of victims. This study documents the effects of continuous immersion in hydrochloric acid (HCl, 37%) on molars using macroscopic analysis, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS). The goal of this study is to aid in distinguishing visually unrecognizable fragments of dental remains when drastic changes in morphology have occurred as a result of acid exposure. Macroscopic, SEM, and EDS analysis were conducted on seven maxillary molars before and after HCl treatment. Molars reduced in weight relative to the length of time immersed in HCl and the dissolution time was over 40 hours longer than reported in previous studies, at just over 66 hours. SEM and EDS analysis showed acid-treated teeth exhibited morphological patterns such as cracking and layering visible at high magnification. Calcium/phosphorous ratios fell within the expected range of 1.6–2.5, indicating that HCl-treated teeth are still identifiable as osseous or dental tissue even when not visually identifiable as teeth. This is the first study to present SEM images of molar cementum before and after immersion in HCl and to present EDS results. This information can assist researchers and investigators in determining the presence of dental tissue in a forensic context associated with acid disposal.
Thanatosensitive Design Exemplars for Embodied Experience of Nonattachment

This positon paper highlights the less supported letting go aspect of the experience of loss and positions it within the HCI work on death and dying. It also argues for the value of embracing nonattachment and accepting impermanence and illustrate this with design exemplars piloted with 4 participants in Japan. Findings emphasize the value of the aesthetic, embodied experience to support the celebration of non-attachment.
Mechanical stretch increases Kv1.5 current through an interaction between the S1–S2 linker and N-terminus of the channel

The voltage-gated potassium channel Kv1.5 plays important roles in atrial repolarization and regulation of vascular tone. In the present study, we investigated the effects of mechanical stretch on Kv1.5 channels. We induced mechanical stretch by centrifuging or culturing Kv1.5-expressing HEK 293 cells and neonatal rat ventricular myocytes in low osmolarity (LO) medium and then recorded Kv1.5 current (IKv1.5) in a normal, isotonic solution. We observed that mechanical stretch increased IKv1.5, and this increase required the intact, long, proline-rich extracellular S1–S2 linker of the Kv1.5 channel. The low osmolarity–induced IKv1.5 increase also required an intact intracellular N terminus, which contains the binding motif for endogenous Src tyrosine kinase that constitutively inhibits IKv1.5. Disrupting the Src-binding motif of Kv1.5 through N-terminal truncation or mutagenesis abolished the mechanical stretch-mediated increase in IKv1.5. Our results further showed that the extracellular S1–S2 linker of Kv1.5 communicates with the intracellular N terminus. Although the S1–S2 linker of WT Kv1.5 could be cleaved by extracellularly applied proteinase K (PK), an N-terminal truncation up to amino acid residue 209 altered the conformation of the S1–S2 linker and made it no longer susceptible to proteinase K–mediated cleavage. In summary, the findings of our study indicate that the S1–S2 linker of Kv1.5 represents a mechanosensor that regulates the activity of this channel. By targeting the S1–S2 linker, mechanical stretch may induce a change in the N-terminal conformation of Kv1.5 that relieves Src-mediated tonic channel inhibition and results in an increase in IKv1.5.
Dyadic nominations of bullying: Comparing types of bullies and their victims.

Previous studies indicate that when identifying individuals involved in bullying, the concordance between self- and peer- reports is low to moderate. There is support that self- and peer- identified victims constitute distinct types of victims and differ in adjustment. Likewise, differentiating between self- and peer- reports of bullying may also reveal distinct types of bullies. The goal of this study was to examine differences between types of bullies identified via dyadic nominations (self-identified, victim-identified, and self/victim identified). First, we examined the concordance between dyadic nominations of bullying and traditional measures of bullying (i.e., self- and peer-reports). Second, we compared the behavioral profiles of the bully types to nonbullies, with a focus on aggressive behaviors and social status. Third, we examined whether the types of bullies targeted victims with different levels of popularity, as well as the role of their own popularity and prioritizing of popularity. Participants were 1,008 Dutch adolescents (50.1% male, Mage = 14.14 years, standard deviation [SD] = 1.30) who completed a classroom assessment of dyadic nominations, peer nominations, and self-report items. Results indicated that victim identified and self/victim identified bullies were more aggressive, more popular, and less socially preferred than self-identified bullies and nonbullies. Self/victim identified bullies targeted victims with the highest social status. The association between bully type and victims' popularity was further qualified by bullies' own popularity and the degree to which they prioritized popularity. Implications for the implementation of dyadic nominations are discussed.
Population collapse and retreat to fire refugia of the Tasmanian endemic conifer Athrotaxis selaginoides following the transition from Aboriginal to European fire management

Untangling the nuanced relationships between landscape, fire disturbance, human agency, and climate is key to understanding rapid population declines of fire‐sensitive plant species. Using multiple lines of evidence across temporal and spatial scales (vegetation survey, stand structure analysis, dendrochronology, and fire history reconstruction), we document landscape‐scale population collapse of the long‐lived, endemic Tasmanian conifer Athrotaxis selaginoides in remote montane catchments in southern Tasmania. We contextualized the findings of this field‐based study with a Tasmanian‐wide geospatial analysis of fire‐killed and unburned populations of the species. Population declines followed European colonization commencing in 1802 ad that disrupted Aboriginal landscape burning. Prior to European colonization, fire events were infrequent but frequency sharply increased afterwards. Dendrochronological analysis revealed that reconstructed fire years were associated with abnormally warm/dry conditions, with below‐average streamflow, and were strongly teleconnected to the Southern Annular Mode. The multiple fires that followed European colonization caused near total mortality of A. selaginoides and resulted in pronounced floristic, structural vegetation, and fuel load changes. Burned stands have very few regenerating A. selaginoides juveniles yet tree‐establishment reconstruction of fire‐killed adults exhibited persistent recruitment in the period prior to European colonization. Collectively, our findings indicate that this fire‐sensitive Gondwanan conifer was able to persist with burning by Aboriginal Tasmanians, despite episodic widespread forest fires. By contrast, European burning led to the restriction of A. selaginoides to prime topographic fire refugia. Increasingly, frequent fires caused by regional dry and warming trends and increased ignitions by humans and lightning are breaching fire refugia; hence, the survival Tasmanian Gondwanan species demands sustained and targeted fire management.
An update on the microbiology, immunology and genetics of seborrheic dermatitis

The underlying mechanism of seborrheic dermatitis (SD) is poorly understood but major scientific progress has been made in recent years related to microbiology, immunology and genetics. In light of this, the major goal of this article was to summarize the most recent articles on SD, specifically related to underlying pathophysiology. SD results from Malassezia hydrolysation of free fatty acids with activation of the immune system by the way of pattern recognition receptors, inflammasome, IL‐1β and NF‐kB. M. restricta and M. globosa are likely the most virulent subspecies, producing large quantities of irritating oleic acids, leading to IL‐8 and IL‐17 activation. IL‐17 and IL‐4 might play a big role in pathogenesis, but this needs to be further studied using novel biologics. No clear genetic predisposition has been established; however, recent studies implicated certain increased‐risk human leucocyte antigen (HLA) alleles, such as A*32, DQB1*05 and DRB1*01 as well as possible associations with psoriasis and atopic dermatitis (AD) through the LCE3 gene cluster while SD, and SD‐like syndromes, shares genetic mutations that appear to impair the ability of the immune system to restrict Malassezia growth, partially due to complement system dysfunction. A paucity of studies exists looking at the relationship between SD and systemic disease. In HIV, SD is thought to be secondary to a combination of immune dysregulation and disruption in skin microbiota with unhindered Malassezia proliferation. In Parkinson's disease, SD is most likely secondary to parasympathetic hyperactivity with increased sebum production as well as facial immobility which leads to sebum accumulation.