Modular design of the selectivity filter pore loop in a novel family of prokaryotic inward rectifier' (NirBac) channels

Potassium channels exhibit a modular design with distinct structural and functional domains; in particular, a highly conserved pore-loop sequence that determines their ionic selectivity. We now report the functional characterisation of a novel group of functionally non-selective members of the prokaryotic inward rectifier' subfamily of K + channels. These channels share all the key structural domains of eukaryotic and prokaryotic Kir/KirBac channels, but instead possess unique pore-loop selectivity filter sequences unrelated to any other known ionic selectivity filter. The strikingly unusual architecture of these NirBac' channels defines a new family of functionally non-selective ion channels, and also provides important insights into the modular design of ion channels, as well as the evolution of ionic selectivity within this superfamily of tetrameric cation channels

Book ownership in Ottoman Sarajevo 1707-1828

This dissertation presents findings on book ownership in Ottoman Sarajevo based on the examination of 59 inheritance inventories recorded in the city court registers (sijills) for the period from 1707 to 1828. It includes a case study of one particular book owner, kadi Ṣāliḥ ‘Izzat Ḥromozāde from Sarajevo, who endowed his book collection in 1828. The findings are placed in the wider social and cultural context of Ottoman Bosnia and the questions of literacy, education, the role of libraries, informal channels for the transmission of knowledge, the use of different languages and scripts, the role of scribes and bookbinders in a largely manuscript culture, and the introduction of print. The dissertation draws on the manuscript of the Chronicle of Mullā Muṣṭafā Basheskī (d. cca 1802), as the major narrative source for the period. It also gathers and presents the references to written culture in Bosnian oral poetry and various folk customs revolving around the use of books in order to illustrate one of the many interfaces between the written and spoken word and to demonstrate the range of functions books could play in a largely oral and illiterate society

Diversity in the digital age: how consumers respond to diverse virtual influencers

In recent years the popularity of social media influencers has grown exponentially, in part because influencers tend to not be seen as advertising and they enable brands to reach engaged audiences. As such, influencer marketing is perceived as an effective and cost-effective marketing tool. However, like all areas of marketing there are broad-based shifts that are having significant effects on the domain of influencer marketing. First, there are calls for greater levels of diversity and broader representation of diverse communities. Second, digital innovation is having a profound effect on the field of influencer marketing, leading to the advent of virtual influencers that are artificially created, often through generative AI. These shifts raise questions about the effect of diversity in influencer marketing – with implications for brands that engage virtual influencers. In this paper, we present two experiments that investigate the effect of diversity representation in the context of virtual influencers. Results show that when brands engage virtual influencers to represent diverse subgroups, novelty and likeability act to mediate positive effects for the influencer (word-of-mouth and follow intentions) and the brand (purchase intentions). Theoretical and practical implications are discussed

Digitaliseringens påverkan på revisionsprocessen. En kvalitativ studie om hur mindre och större revisionsföretag påverkas av digitalisering

Bakgrund och problembeskrivning: Revisionsprocessen har påverkats av digitaliseringen genom att arbetsprocesser och teknikanvändning förändras. Detta har medfört både fördelar och utmaningar för revisionsföretag i olika storlekar. Mindre företag kan ha problem med resurser och införande av ny teknik, medan större företag kan utnyttja sina omfattande resurser för att anpassa och förbättra sina digitala verktyg. Syfte: Syftet med studien är att analysera hur digitaliseringen påverkat revisionsprocessen och undersöka eventuella skillnader mellan mindre och större revisionsföretag. Huvudfokus ligger på att identifiera de främsta följderna, utmaningarna och möjligheterna som digitaliseringen medför för dessa företag. Metod:.En kvalitativ forskningsmetod har tillämpats, där information har samlats in genom semistrukturerade intervjuer med revisorer från både mindre och större revisionsbyråer. Analysen grundar sig på dessa intervjuer samt en granskning av relevant litteratur och branschrapporter. Resultat och slutsats: Genom att använda digitala verktyg har det visat sig att effektiviteten och noggrannheten i revisionsprocessen förbättrats. Men det finns också utmaningar, såsom behovet av kontinuerlig kompetensutveckling, datasäkerhet och upprätthållande av professionella granskningsstandarder. De större revisionsföretagen har fördelen av att ha resurser att investera i avancerad teknologi som AI och maskininlärning, vilket kan effektivisera processen och förbättra datahanteringen. Mindre företag kan dock använda molnbaserade lösningar för att förbli konkurrenskraftiga, trots resursbegränsningar. Studien visar att digitaliseringen omformar revisionsyrket och skiftar fokus från manuell datahantering till mer strategiska rådgivningsroller. Detta kräver ständig kompetensutveckling, utbildning och anpassning till ny teknologi

Glia, sympathetic activity and cardiovascular disease

New Findings What is the topic of this review? In this review, we discuss recent findings that provide a novel insight into the mechanisms that link glial cell function with the pathogenesis of cardiovascular disease, including systemic arterial hypertension and chronic heart failure. What advances does it highlight? We discuss how glial cells may influence central presympathetic circuits, leading to maladaptive and detrimental increases in sympathetic activity and contributing to the development and progression of cardiovascular disease. Increased activity of the sympathetic nervous system is associated with the development of cardiovascular disease and may contribute to its progression. Vasomotor and cardiac sympathetic activities are generated by the neuronal circuits located in the hypothalamus and the brainstem. These neuronal networks receive multiple inputs from the periphery and other parts of the CNS and, at a local level, may be influenced by their non-neuronal neighbours, in particular glial cells. In this review, we discuss recent experimental evidence suggesting that astrocytes and microglial cells are able to modulate the activity of sympathoexcitatory neural networks in disparate physiological and pathophysiological conditions. We focus on the chemosensory properties of astrocytes residing in the rostral ventrolateral medulla oblongata and discuss signalling mechanisms leading to glial activation during brain hypoxia and inflammation. Alterations in these mechanisms may lead to heightened activity of sympathoexcitatory CNS circuits and contribute to maladaptive and detrimental increases in sympathetic tone associated with systemic arterial hypertension and chronic heart failure

Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment

Background: Cannabinoids are often prescribed for neuropathic pain, but the evidence-based recommendation is ‘weak against’. Objectives: The aim was to examine the effect of two cannabinoids and their combination in peripheral neuropathic pain. Methods: This was a randomized, double-blind, trial with treatment arms for cannabidiol (CBD), tetra-hydro-cannabinol (THC), CBD and THC combination (CBD/THC), and placebo in a 1:1:1:1 ratio and flexible drug doses (CBD 5–50 mg, THC 2.5–25 mg, and CBD/THC 5 mg/2.5 mg–50 mg/25 mg). Treatment periods of 8-week duration were proceeded by 1 week for baseline observations. Patients with painful polyneuropathy, post-herpetic neuralgia and peripheral nerve injury (traumatic or surgical) failing at least one previous evidence-based pharmacological treatment were eligible for inclusion. The primary outcome was the change in weekly average of daily pain measured with a numeric rating scale (NRS). Trail Making Test (TMT) was used as one of the tests of mental functioning. Results: In all, 145 patients were included in the study of which 118 were randomized and 115 included in the intention-to-treat analysis. None of the treatments reduced pain compared to placebo (p = 0.04–0.60). Effect sizes as estimated in week 8 (positive values worse and negative better than placebo) were CBD mean 1.14 NRS points (95% CI 0.11–2.19), THC 0.38 (CI −0.65 to 1.4) and CBD/THC −0.12 (−1.13 to 0.89). Conclusions: CBD, THC and their combination did not relieve peripheral neuropathic pain in patients failing at least one previous evidence-based treatment for neuropathic pain.</p

Increased Abundance of Lactobacillales in the Colon of Beta-Adrenergic Receptor Knock Out Mouse Is Associated With Increased Gut Bacterial Production of Short Chain Fatty Acids and Reduced IL17 Expression in Circulating CD4+ Immune Cells

Emerging evidence suggests an associative link between gut dysbiosis, the autonomic nervous system (ANS) and the immune system in pathophysiology of neurogenic hypertension (HTN). However, the close interplay between these three systems presents us with difficulties in deciphering the cause-effect relationship in disease. The present study utilized beta 1 and 2 adrenergic receptor knock out (AdrB1tm1BkkAdrB2tm1Bkk/J KO) mice to isolate the effects of reduced overall sympathetic drive on gut microbiota and systemic immune system. We observed the following: (i) Diminished beta adrenergic signaling mainly reflects in shifts in the Firmicutes phyla, with a significant increase in abundance of largely beneficial Bacilli Lactobacillales in the KO mice; (ii) This was associated with increased colonic production of beneficial short chain fatty acids (SCFAs) butyrate, acetate and propionate, confirming functional microbiota shifts in the KO mice; (iii) Dampened systemic immune responses in the KO mice reflected in reduction on circulating CD4+.IL17+ T cells and increase in young neutrophils, both previously associated with shifts in the gut microbiota. Taken together, these observations demonstrate that reduced expression of beta adrenergic receptors may lead to beneficial shifts in the gut microbiota and dampened systemic immune responses. Considering the role of both in hypertension, this suggests that dietary intervention may be a viable option for manipulation of blood pressure via correcting gut dysbiosis