Miracle-dz/UniFAR-FTUs huggingface dataset:
Botulinum neurotoxin type B uses a distinct entry pathway mediated by CDC42 into intestinal cells versus neuronal cells

Botulinum neurotoxins (BoNTs) are responsible for severe flaccid paralysis by inhibiting the release of acetylcholine at the neuromuscular junctions. BoNT type B (BoNT/B) most often induces mild forms of botulism with predominant dysautonomic symptoms. In food borne botulism and botulism by intestinal colonisation such as infant botulism, which are the most frequent naturally acquired forms of botulism, the digestive tract is the main entry route of BoNTs into the organism. We previously showed that BoNT/B translocates through mouse intestinal barrier by an endocytosis‐dependent mechanism and subsequently targets neuronal cells, mainly cholinergic neurons, in the intestinal mucosa and musculosa. Here, we investigated the entry pathway of BoNT/B using fluorescent C‐terminal domain of the heavy chain (HcB), which is involved in the binding to specific receptor(s) and entry process into target cells. While the combination of gangliosides GD1a/GD1b/GT1b and synaptotagmin I and to a greater extent synaptotagmin II constitutes the functional HcB receptor on NG108‐15 neuronal cells, HcB only uses the gangliosides GD1a/GD1b/GT1b to efficiently bind to m‐ICcl2 intestinal cells. HcB enters both cell types by a dynamin‐dependent endocytosis, which is efficiently prevented by Dynasore, a dynamin inhibitor, and reaches a common early endosomal compartment labeled by early endosome antigen (EEA1). In contrast to neuronal cells, HcB uses a Cdc42‐dependent pathway to enter intestinal cells. Then, HcB is transported to late endosomes in neuronal cells, whereas it exploits a nonacidified pathway from apical to basal lateral side of m‐ICcl2 cells supporting a transcytotic route in epithelial intestinal cells.
E3 Ubiquitin Ligases: Key Regulators of Hormone Signaling in Plants*

Ubiquitin-mediated control of protein stability is central to most aspects of plant hormone signaling. Attachment of ubiquitin to target proteins occurs via an enzymatic cascade with the final step being catalyzed by a family of enzymes known as E3 ubiquitin ligases, which have been classified based on their protein domains and structures. Although E3 ubiquitin ligases are conserved among eukaryotes, in plants they are well-known to fulfill unique roles as central regulators of phytohormone signaling, including hormone perception and regulation of hormone biosynthesis. This review will highlight up-to-date findings that have refined well-known E3 ligase-substrate interactions and defined novel E3 ligase substrates that mediate numerous hormone signaling pathways. Additionally, examples of how particular E3 ligases may mediate hormone crosstalk will be discussed as an emerging theme. Looking forward, promising experimental approaches and methods that will provide deeper mechanistic insight into the roles of E3 ubiquitin ligases in plants will be considered.
Design solutions for securing SRAM cell against power analysis

Side channel attacks exploit physical imperfections of hardware to circumvent security features achieved by mathematically secure protocols and algorithms. This is achieved by monitoring physical quantities, usually power consumption or electromagnetic radiation, which contain information about the secret data. As a countermeasure, several circuit styles have been proposed for designing side-channel resistant logic gates and flip-flops. However, little effort has been made to develop secure memory arrays. An SRAM cell with 8 transistors has been proposed in order to obtain power analysis resistance by using a dual-rail precharge principle, the same technique used in various secure logic styles. In this paper we look into the practical aspects of this cell such as noise margins, layout strategy and read current. In addition, we propose alternative solutions for power-analysis resistant SRAM. We compare these solutions in terms of data stability, delay and side-channel resistance.
P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro

Summary Patients with chronic renal failure (CRF) exhibit endothelial dysfunction, which may involve uremic retention solutes that accumulate in blood and tissues. In this study, we investigated the in vitro effect of the uremic retention solute p-cresol on the barrier function of endothelial cells (HUVEC). P-cresol was tested at concentrations found in CRF patients, and since p-cresol is protein-bound, experiments were performed with and without physiological concentration of human albumin (4 g/dl). With albumin, we showed that p-cresol caused a strong increase in endothelial permeability after a 24-hour exposure. Concomitant with this increase in endothelial permeability, p-cresol induced a reorganization of the actin cytoskeleton and an alteration of adherens junctions. These molecular events were demonstrated by the decreased staining of cortical actin, associated with the formation of stress fibers across the cell, and by the decreased staining of junctional VE-cadherin. This decrease in junctional VE-cadherin staining was not associated with a reduction of membrane expression. Without albumin, the effects of p-cresol were more pronounced. The specific Rho kinase inhibitor, Y-27632, inhibited the effects of p-cresol, indicating that p-cresol mediates the increase in endothelial permeability in a Rho kinase-dependent way. In conclusion, these results show that p-cresol causes a severe dysfunction of endothelial barrier function in vitro and suggest this uremic retention solute may participate in the endothelium dysfunction observed in CRF patients.
Effects of noise on the well-being of railway staff

The present study involved a survey of over 1,000 rail staff and the objective was to determine the effects of noise on well-being. One of the major problems with noise surveys has been the lack of control of confounding factors and the present study used a measuring instrument (the Smith Well-being Questionnaire - SWELL) that records information on demographics, lifestyle and personality, as well as job characteristics. The outcomes measured included illness caused or made worse by work, presenteeism, mental health problems, musculo-skeletal disorders, stress at work, job satisfaction, fatigue, work-life balance and life stress. Over 40% of the sample reported frequent exposure to high levels of noise and in some jobs this was much higher. After controlling for possible confounders, noise was found to predict fatigue at work, job satisfaction, presenteeism, musculo-skeletal disorders, illness caused or made worse by work, work-life balance, life stress and general anxiety/depression. These findings suggest that noise reduces the well-being of railway staff. Further research is needed on the non-auditory effects of the frequent and loud noise exposure in this transport sector.
The Role of 5-HTR6 in Mossy Fiber Sprouting: Activating Fyn and p-ERK1/2 in Pilocarpine-Induced Chronic Epileptic Rats

Objective: Our primary objective is to verify whether 5-HTR6 is involved in the development of mossy fiber sprouting (MFS), and to determine how the progression of MFS is affected by 5-HTR6. Methods: A total of 90 male adult Sprague-Dawley rats were allocated into either the control group (n=36) or the epileptic group (n=54). Status epilepticus (SE) of rats was induced by the intraperitoneal (i.p.) injection of LiCl-pilocarpine. We conducted our experiments in two stages. The first stage involves equally dividing 36 epileptic rats into three groups with treatments of none, 5-HTR6 antagonist SB-27104 (SB) and vehicle DMSO. Then behavior and electroencephalogram (EEG) of rats were monitored by video-EEG. The second stage involves dividing 126 epileptic rats into seven groups with treatments of none, 10% DMSO, SB (100 µg/kg), Fyn antagonist PP2 (50 µg/kg), p-ERK1/2 antagonist PD-98059 (30 µg/kg), SB (100 µg/ kg) + PP2 (50 µg/kg); SB (100 µg/kg) + PD-98059 (30 µg/kg). We also treated 18 rats in the control group of the first stage with 100 µg/kg 5-HTR6 agonist WAY-181187 (WAY). MFS of rats was detected through the approach of Timm’s staining. Finally, expressions of 5-HTR6, Fyn, p-ERK1/2 and GAP-3 were qualified and semi-quantified via western blotting or RT-PCR. Results: Induction of SE could stimulate formation of MFS and increased GAP-43 expressions. Expressions of 5-HTR6, Fyn and p-ERK1/2 were also up-regulated with increasing time after establishment of SE models. The development of MFS was remarkably inhibited by SB, PP2 and PD. Compared to the single antagonist, such an inhibitory effect was enhanced by SB+PD or SB+PP. Moreover, treatment of healthy rats with WAY would contribute to up-regulated Fyn and p-ERK1/2 expressions, as well as development of MFS (P < 0.05). Suppression of Fyn triggered a down-regulating trend of p-ERK1/2 (P < 0.05), however, suppressed p-ERK1/2 did not have such a significant effect on Fyn expression. Conclusion: HTR6 may affect the progression of MFS by activating both p-ERK1/2 and Fyn, which further modulate the expression of GAP-43.
Who’s the Leader, Mania or Depression? Predominant Polarity and Alcohol/Polysubstance Use in Bipolar Disorders

Background: Predominant polarity characterises patients who mainly manifest recurrences of depression or mania/hypomania. Alcohol use disorder (AUD) and polysubstance use (PSU), which often complicate bipolar disorder (BD) and affect its clinical course, can influence predominant polarity. Nevertheless, previous studies have not clarified if BD patients differ in predominant polarity from BD patients with substance use disorder (SUD) comorbidity. Objective: The aim of this study was to compare predominant polarity between BD without SUD, BD with AUD and BD with PSU. We also investigated the association between predominant polarity and first episode polarity in each diagnostic group. Method: We evaluated predominant polarity (≥2:1 lifetime depressive vs. manic/hypomanic episodes) in 218 DSM-IV-TR BD patients. Specifically, data were obtained from 86 patients with BD without SUD, 69 patients with BD and AUD, and 63 patients with BD and PSU with alcohol as the primary substance abused. Results: The three groups significantly differed for predominant polarity. The most common predominant polarity in BD without SUD was manic, while in BD with AUD and in BD with PSU it was depressive. Uncertain predominant polarity was the least common in BD without SUD and BD with PSU, whereas in BD with AUD, manic predominant polarity was least common. Predominant polarity matched onset polarity in all groups. Conclusion: BD without SUD, BD with AUD, and BD with PSU have different predominant polarities. The correspondence between predominant polarity and polarity at the onset may impact diagnosis and treatment of BD.
C1q and Mannose-Binding Lectin Interact with CR1 in the Same Region on CCP24-25 Modules

Complement receptor type 1 (CR1) is a multi modular membrane receptor composed of 30 homologous complement control protein modules (CCP) organized in four different functional regions called long homologous repeats (LHR A, B, C, and D). CR1 is a receptor for complement-opsonins C3b and C4b and specifically interacts through pairs of CCP modules located in LHR A, B, and C. Defense collagens such as mannose-binding lectin (MBL), ficolin-2, and C1q also act as opsonins and are involved in immune clearance through binding to the LHR-D region of CR1. Our previous results using deletion variants of CR1 mapped the interaction site for MBL and ficolin-2 on CCP24-25. The present work aimed at deciphering the interaction of C1q with CR1 using new CR1 variants concentrated around CCP24-25. CR1 bimodular fragment CCP24-25 and CR1 CCP22-30 deleted from CCP24-25 produced in eukaryotic cells enabled to highlight that the interaction site for both MBL and C1q is located on the same pair of modules CCP24-25. C1q binding to CR1 shares with MBL a main common interaction site on the collagen stalks but also subsidiary sites most probably located on C1q globular heads, contrarily to MBL.
Recurrence Quantification for the Analysis of Coupled Processes in Aging

Objectives Aging is a complex phenomenon, with numerous simultaneous processes that interact with each other on a moment-to-moment basis. One way to quantify the interactions of these processes is by measuring how much a process is similar to its own past states or the past states of another system through the analysis of recurrence. This paper presents an introduction to recurrence quantification analysis (RQA) and cross-recurrence quantification analysis (CRQA), two dynamical systems analysis techniques that provide ways to characterize the self-similar nature of each process and the properties of their mutual temporal co-occurrence. Method We present RQA and CRQA and demonstrate their effectiveness with an example of conversational movements across age groups. Results RQA and CRQA provide methods of analyzing the repetitive processes that occur in day-to-day life, describing how different processes co-occur, synchronize, or predict each other and comparing the characteristics of those processes between groups. Discussion With intensive longitudinal data becoming increasingly available, it is possible to examine how the processes of aging unfold. RQA and CRQA provide information about how one process may show patterns of internal repetition or echo the patterning of another process and how those characteristics may change across the process of aging.
Prognostic relevance of mitral and tricuspid regurgitation in patients with severe aortic stenosis

Aims Although concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) are frequently present in patients with aortic stenosis (AS), outcome data are scarce and treatment strategies are controversial. The aim of the present study was to assess the presentation and outcome of patients with AS and coexisting MR and TR. Methods and results Eighty-nine consecutive patients with severe AS and at least moderate MR (72 functional and 17 degenerative) were included and followed. Seventy-five patients were symptomatic at presentation. Sixty of these had severe symptoms (New York Heart Association class ≥3). Nine additional patients had an indication for valve procedures during follow-up. However, 35 patients were managed conservatively. Isolated aortic valve intervention was performed in 29 patients (22 valve replacement and 7 transcatheter aortic valve replacement) and concomitant mitral valve surgery in 20 patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed: adjusted survival was significantly higher for patients undergoing any valve procedure as compared with patients managed conservatively (P = 0.032). Surgical treatment of severe concomitant MR was associated with improved survival in an unadjusted population but did not reach statistical significance after propensity adjustment. 14 of 36 patients who had concomittant moderate-to-severe tricuspid regurgitation (TR) underwent surgery of which 7 (50 %) died within 3 months postoperatively. On the other hand, only 1 of 35 (3%) with no or mild TR undergoing surgery died within 3 months post-operatively (P < 0.001). Conclusion Presence of MR in patients with severe AS characterizes a high-risk population. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy.
Manipulation of the Host Cell Membrane during Plasmodium Liver Stage Egress

ABSTRACT A crucial step in the life cycle of Plasmodium parasites is the transition from the liver stage to the blood stage. Hepatocyte-derived merozoites reach the blood vessels of the liver inside host cell-derived vesicles called merosomes. The molecular basis of merosome formation is only partially understood. Here we show that Plasmodium berghei liver stage merozoites, upon rupture of the parasitophorous vacuole membrane, destabilize the host cell membrane (HCM) and induce separation of the host cell actin cytoskeleton from the HCM. At the same time, the phospholipid and protein composition of the HCM appears to be substantially altered. This includes the loss of a phosphatidylinositol 4,5-bisphosphate (PIP2) reporter and the PIP2-dependent actin-plasma membrane linker ezrin from the HCM. Furthermore, transmembrane domain-containing proteins and palmitoylated and myristoylated proteins, as well as glycosylphosphatidylinositol-anchored proteins, lose their HCM localization. Collectively, these findings provide an explanation of HCM destabilization during Plasmodium liver stage egress and thereby contribute to our understanding of the molecular mechanisms that lead to merosome formation. IMPORTANCE Egress from host cells is an essential process for intracellular pathogens, allowing successful infection of other cells and thereby spreading the infection. Here we describe the molecular details of a novel egress strategy of Plasmodium parasites infecting hepatocytes. We show that toward the end of the liver stage, parasites induce a breakdown of the host cell actin cytoskeleton, leading to destabilization of the host cell plasma membrane. This, in turn, results in the formation of membrane vesicles (merosomes), in which parasites can safely migrate from liver tissue to the bloodstream to infect red blood cells and start the pathogenic phase of malaria. IMPORTANCE Egress from host cells is an essential process for intracellular pathogens, allowing successful infection of other cells and thereby spreading the infection. Here we describe the molecular details of a novel egress strategy of Plasmodium parasites infecting hepatocytes. We show that toward the end of the liver stage, parasites induce a breakdown of the host cell actin cytoskeleton, leading to destabilization of the host cell plasma membrane. This, in turn, results in the formation of membrane vesicles (merosomes), in which parasites can safely migrate from liver tissue to the bloodstream to infect red blood cells and start the pathogenic phase of malaria.
An introduction into autonomic nervous function

The results of many medical measurements are directly or indirectly influenced by the autonomic nervous system (ANS). For example pupil size or heart rate may demonstrate striking moment-to-moment variability. This review intends to elucidate the physiology behind this seemingly unpredictable system. The review is split up into: 1. The peripheral ANS, parallel innervation by the sympathetic and parasympathetic branches, their transmitters and co-transmitters. It treats questions like the supposed sympatho/vagal balance, organization in plexuses and the ‘little brains’ that are active like in the enteric system or around the heart. Part 2 treats ANS-function in some (example-) organs in more detail: the eye, the heart, blood vessels, lungs, respiration and cardiorespiratory coupling. Part 3 poses the question of who is directing what? Is the ANS a strictly top-down directed system or is its organization bottom-up? Finally, it is concluded that the ‘noisy numbers’ in medical measurements, caused by ANS variability, are part and parcel of how the system works. This topical review is a one-man’s undertaking and may possibly give a biased view. The author has explicitly indicated in the text where his views are not (yet) supported by facts, hoping to provoke discussion and instigate new research.
A Type III Effector NleF from EHEC Inhibits Epithelial Inflammatory Cell Death by Targeting Caspase-4

Enterohemorrhagic E. coli (EHEC) is a highly pathogenic bacterial strain capable of inducing severe gastrointestinal disease. Here, we show that EHEC uses the T3SS effector NleF to counteract the host inflammatory response by dampening caspase-4-mediated inflammatory epithelial cell death and by preventing the production of IL-1β. The other two inflammatory caspases, caspase-1 and caspase-5, are not involved in EHEC ΔnleF-induced inflammatory cell death. We found that NleF not only interrupted the heterodimerization of caspase-4-p19 and caspase-4-p10, but also inhibited the interaction of caspase-1 and caspase-4. The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death.
Advancing the damage tolerance of laser beam welded steels using crenellation technique

Fatigue life extension, via the retardation of a growing crack under cyclic loading conditions, has been an important issue for designers and operators to reduce the cost and to improve the structural safety of welded structures. The methods to be employed for retarding fatigue crack propagation, needless to say, should ideally be knowledge based and practical (i.e. easy to implement, cost effective and should not lead to weight increase etc.). In this study, a novel approach based on modifying the distribution of the stress intensity factor (SIF) in plates using thickness variations is presented. By varying thickness via the introduction of ribs, “crenellations”, on one side or surface of the welded or non-welded plates, it was shown that this novel technique can contribute to the fatigue crack propagation life of plates substantially. Furthermore, crenellations can potentially lead to weight reduction for a given target fatigue crack propagation life as well. This research programme aimed to gain a fundamental understanding of the mechanisms involved in the damage tolerance behaviour of crenellated parent material and laser beam welded steel plates which operate, in principle, under cyclic loading. Particular emphasis was given to describe the crack growth retardation mechanism using the crenellation technique. The “crenellations” were introduced on the surface of the steel sheets and plates of medium grade and high-strength steels with and without laser beam welds. Experiments were conducted to study and investigate the fracture toughness, fatigue response and fatigue life of crenellated plates. In parallel, numerical analyses were carried out to compute the actual SIF for the combinations of crenellations in order to correlate the fatigue crack growth data. Investigations focused on fatigue crack propagation (FCP) under constant amplitude loadings, with cracks growing within (in butt joints) and towards (in fillet joints) the fusion zone. A number of crenellation configurations was investigated and the fatigue crack growth data were correlated using SIF. It was shown that the edge regions -where the thickness sharply changes from thin to thick or vice versaand crack length have a substantial effect on the retardation and acceleration of the fatigue cracks. Factors such as sudden thickness variation and crack lengths -where plasticity can be substantial depending on the load levelaffect crack retardation. However, it was shown that the evaluation of the correct SIF with respect to thickness and crack length conveniently describes fatigue cracking in these crenellated plates and allows the behaviour of these plates under cyclic loads to be compared with the behaviour of the reference, as-received plates subject to the same conditions. Based on the present tests and analyses, it is expected that an improvement in the fatigue crack propagation life of crenellated plates can be as much as 50 120 % depending on the configuration