Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells

Microbiota drive tertiary lymphoid tissue formation in mice lacking the nuclear hormone receptor Rorγt, leading to intestinal inflammation and wasting disease

Development of chemical tools based on GSK-7975A to study store-operated calcium entry in cells.

Many physiological functions, such as cell differentiation, proliferation, muscle contraction, neurotransmission and fertilisation, are regulated by changes of Ca2+ levels. The major Ca2+ store in cells is the endoplasmic reticulum (ER). Certain cellular processes induce ER store depletion, e.g. by activating IP3 receptors, that in turn induces a store refilling process known as store-operated calcium entry (SOCE). This refilling process entails protein-protein interactions between Ca2+ sensing stromal interaction molecules (STIM) in the ER membrane and Orai proteins in the plasma membrane. Fully assembled STIM/Orai complexes then form highly selective Ca2+ channels called Ca2+ release-activated Ca2+ Channels (CRAC) through which Ca2+ ions flow into the cytosol and subsequently are pumped into the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Abnormal SOCE has been associated with numerous human diseases and cancers, and therefore key players STIM and Orai have attracted significant therapeutic interest. Several potent experimental and clinical candidate compounds have been developed and have helped to study SOCE in various cell types. We have synthesized multiple novel small-molecule probes based on the known SOCE inhibitor GSK-7975A. Here we present GSK-7975A derivatives, which feature photo-caging, photo-crosslinking, biotin and clickable moieties, and also contain deuterium labels. Evaluation of these GSK-7975A probes using a fluorometric imaging plate reader (FLIPR)-Tetra-based Ca2+ imaging assay showed that most synthetic modifications did not have a detrimental impact on the SOCE inhibitory activity. The photo-caged GSK-7975A was also used in patch-clamp electrophysiology experiments. In summary, we have developed a number of active, GSK-7975A-based molecular probes that have interesting properties and therefore are useful experimental tools to study SOCE in various cells and settings

Problematic use of the Internet is a unidimensional quasi-trait with impulsive and compulsive subtypes

Abstract: Background: Problematic use of the Internet has been highlighted as needing further study by international bodies, including the European Union and American Psychiatric Association. Knowledge regarding the optimal classification of problematic use of the Internet, subtypes, and associations with clinical disorders has been hindered by reliance on measurement instruments characterized by limited psychometric properties and external validation. Methods: Non-treatment seeking individuals were recruited from the community of Stellenbosch, South Africa (N = 1661), and Chicago, United States of America (N = 827). Participants completed an online version of the Internet Addiction Test, a widely used measure of problematic use of the Internet consisting of 20-items, measured on a 5-point Likert-scale. The online questions also included demographic measures, time spent engaging in different online activities, and clinical scales. The psychometric properties of the Internet Addiction Test, and potential problematic use of the Internet subtypes, were characterized using factor analysis and latent class analysis. Results: Internet Addiction Test data were optimally conceptualized as unidimensional. Latent class analysis identified two groups: those essentially free from Internet use problems, and those with problematic use of the Internet situated along a unidimensional spectrum. Internet Addiction Test scores clearly differentiated these groups, but with different optimal cut-offs at each site. In the larger Stellenbosch dataset, there was evidence for two subtypes of problematic use of the Internet that differed in severity: a lower severity “impulsive” subtype (linked with attention-deficit hyperactivity disorder), and a higher severity “compulsive” subtype (linked with obsessive-compulsive personality traits). Conclusions: Problematic use of the Internet as measured by the Internet Addiction Test reflects a quasi-trait - a unipolar dimension in which most variance is restricted to a subset of people with problems regulating Internet use. There was no evidence for subtypes based on the type of online activities engaged in, which increased similarly with overall severity of Internet use problems. Measures of comorbid psychiatric symptoms, along with impulsivity, and compulsivity, appear valuable for differentiating clinical subtypes and could be included in the development of new instruments for assessing the presence and severity of Internet use problems

Climate change and cropland management compromise soil integrity and multifunctionality

Soils provide essential ecosystem functions that are threatened by climate change and intensified land use. We explore how climate and land use impact multiple soil function simultaneously, employing two datasets: (1) observational – 456 samples from the European Land Use/Land Cover Area Frame Survey; and (2) experimental – 80 samples from Germany’s Global Change Experimental Facility. We aim to investigate whether manipulative field experiment results align with observable climate, land use, and soil multifunctionality trends across Europe, measuring seven ecosystem functions to calculate soil multifunctionality. The observational data showed Europe-wide declines in soil multifunctionality under rising temperatures and dry conditions, worsened by cropland management. Our experimental data confirmed these relationships, suggesting that changes in climate will reduce soil multifunctionality across croplands and grasslands. Land use changes from grasslands to croplands threaten the integrity of soil systems, and enhancing soil multifunctionality in arable systems is key to maintain multifunctionality in a changing climate

Problematic internet use (PIU): Associations with the impulsive-compulsive spectrum. An application of machine learning in psychiatry.

Problematic internet use is common, functionally impairing, and in need of further study. Its relationship with obsessive-compulsive and impulsive disorders is unclear. Our objective was to evaluate whether problematic internet use can be predicted from recognised forms of impulsive and compulsive traits and symptomatology. We recruited volunteers aged 18 and older using media advertisements at two sites (Chicago USA, and Stellenbosch, South Africa) to complete an extensive online survey. State-of-the-art out-of-sample evaluation of machine learning predictive models was used, which included Logistic Regression, Random Forests and Naïve Bayes. Problematic internet use was identified using the Internet Addiction Test (IAT). 2006 complete cases were analysed, of whom 181 (9.0%) had moderate/severe problematic internet use. Using Logistic Regression and Naïve Bayes we produced a classification prediction with a receiver operating characteristic area under the curve (ROC-AUC) of 0.83 (SD 0.03) whereas using a Random Forests algorithm the prediction ROC-AUC was 0.84 (SD 0.03) [all three models superior to baseline models p < 0.0001]. The models showed robust transfer between the study sites in all validation sets [p < 0.0001]. Prediction of problematic internet use was possible using specific measures of impulsivity and compulsivity in a population of volunteers. Moreover, this study offers proof-of-concept in support of using machine learning in psychiatry to demonstrate replicability of results across geographically and culturally distinct settings.This research received internal departmental funds of the Department of Psychiatry at the University of Chicago.This is the final version of the article. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.jpsychires.2016.08.010

Organometallic-Organic Hybrid Polymers Assembled from Pentaphosphaferrocene, Bipyridyl Linkers, and Cul Ions

A multicomponent approach of the P-n ligand complex [Cp*Fe((5)-P-5)] (1: Cp* = (5)-C5Me5) with the ditopic organic linkers 4,4-bipyridine (2) or trans-1,2-di(pyridine-4-yl)ethene (3) in the presence of Cu-I salts of the anions [BF4](-) and [PF6](-) or the coordinating anion Br-, leads to the formation of four novel organometallic-organic hybrid polymers: the cationic 1D polymeric compounds [Cu-4{Cp*Fe(mu(3),(5:1:1)-P-5)}(2)(mu,(1:1)-C10H8N2)(4)(CH3CN)(4)](n)[BF4](4n) (4) and [Cu-4{Cp*Fe(mu(3),(5:1:1)-P-5)}(2)(mu,(1:1)-C10H8N2)(4)(CH3CN)(4)](n)[PF6](4n) (5) as well as the unique neutral threefold 2D 2D interpenetrated networks [Cu2Cl2{Cp*Fe(mu(3),(5:1:1)-P-5)}(mu,(1:1)-C12H10N2)](n) (6) and [Cu2Br2{Cp*Fe(mu(3),(5:1:1)-P-5)}(mu,(1:1)-C10H8N2)](n) (7)

Studienprotokoll: Register zur Prognose akut-symptomatischer Anfälle (PROSA-Register) – eine prospektive multizentrische Beobachtungsstudie

Background: Acute symptomatic epileptic seizures occur in close temporal relation to an acute disturbance of brain function. They are associated with a low risk of subsequent unprovoked seizures; thus, current guidelines recommend not to administer a long-term antiseizure medication; however, in clinical practice long-term secondary seizure prophylaxis is frequently initiated. The seizure prognosis after guideline-conform untreated or only briefly treated acute symptomatic seizures, is so far unknown. Hypothesis: Following an acute symptomatic first epileptic seizure of structural etiology, the 1-year risk of subsequent unprovoked seizures is not higher than 25%, even if antiseizure medication was not applied or for a short period only. Methods: The PROSE register is a single-arm, open, prospective, multicenter observational study. A total of 115 subjects aged 18 years or older with an acute symptomatic first epileptic seizure of structural etiology will be included if the seizure was not a status epilepticus. Intrahospital follow-up will be based on the hospital records. Telephone follow-up interviews will be conducted 3, 6, and 12 months after the acute symptomatic seizure. Discussion: The PROSE register will shed light on current treatment practice of acute symptomatic seizures and the actual seizure outcome within 1 year. The results are assumed to support the current evidence that giving antiseizure medication for a longer period of time exceeding the acute phase of the underlying condition is unnecessary

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11034-w

COVID-19 and Intracranial Hemorrhage: A Multicenter Case Series, Systematic Review and Pooled Analysis

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future