“A thematic choice started as an escape route”Autobiographic sketch by Zsuzsa Urbach

2003 ◽  
Vol 44 (1) ◽  
pp. 10-11
Author(s):  
Zsuzsa Urbach
Keyword(s):  
Author(s):  
Juan Carlos Polanco ◽  
Gabriel Rhys Hand ◽  
Adam Briner ◽  
Chuanzhou Li ◽  
Jürgen Götz

AbstractThe microtubule-associated protein tau has a critical role in Alzheimer’s disease and other tauopathies. A proposed pathomechanism in the progression of tauopathies is the trans-synaptic spreading of tau seeds, with a role for exosomes which are secretory nanovesicles generated by late endosomes. Our previous work demonstrated that brain-derived exosomes isolated from tau transgenic rTg4510 mice encapsulate tau seeds with the ability to induce tau aggregation in recipient cells. We had also shown that exosomes can hijack the endosomal pathway to spread through interconnected neurons. Here, we reveal how tau seeds contained within internalized exosomes exploit mechanisms of lysosomal degradation to escape the endosome and induce tau aggregation in the cytosol of HEK293T-derived ‘tau biosensor cells’. We found that the majority of the exosome-containing endosomes fused with lysosomes to form endolysosomes. Exosomes induced their permeabilization, irrespective of the presence of tau seeds, or whether the exosomal preparations originated from mouse brains or HEK293T cells. We also found that permeabilization is a conserved mechanism, operating in both non-neuronal tau biosensor cells and primary neurons. However, permeabilization of endolysosomes only occurred in a small fraction of cells, which supports the notion that permeabilization occurs by a thresholded mechanism. Interestingly, tau aggregation was only induced in cells that exhibited permeabilization, presenting this as an escape route of exosomal tau seeds into the cytosol. Overexpression of RAB7, which is required for the formation of endolysosomes, strongly increased tau aggregation. Conversely, inhibition of lysosomal function with alkalinizing agents, or by knocking-down RAB7, decreased tau aggregation. Together, we conclude that the enzymatic activities of lysosomes permeabilize exosomal and endosomal membranes, thereby facilitating access of exosomal tau seeds to cytosolic tau to induce its aggregation. Our data underscore the importance of endosomal membrane integrity in mechanisms of cellular invasion by misfolded proteins that are resistant to lysosomal degradation.


2021 ◽  
Vol 13 (14) ◽  
pp. 7903
Author(s):  
Young-Hoon Bae ◽  
Jong-Yeong Son ◽  
Ryun-Seok Oh ◽  
Hye-Kyoung Lee ◽  
Yoon-Ha Lee ◽  
...  

This study analyzed the decision-making times (DMTs) of participants at T-type indoor intersections according to the horizontal/vertical installation locations and the arrow directions of escape route signs. A total of 120 university students participated in the study. We analyzed the DMTs and following rates (FRs) required for the participants to observe the visual stimuli of the signs installed in front of the T-type indoor intersections and then properly select a path according to the arrow direction of the signs. The results are as follows: (1) the participants exhibited shorter DMTs for the right arrow direction of the signs, (2) the Simon effect occurred when the horizontal installation location of the signs was more than 60 cm away from the center of the T-type indoor intersection on both sides, (3) the DMTs of participants increased when the vertical installation location of the signs was low. Finally, we proposed an optimal installation location of the signs to support the shortest DMTs at T-type indoor intersections. It is expected that the results of this study will provide a database of DMTs, based on the locations of the signs during emergency evacuations, and will be utilized to improve the installation guidelines and regulations of signs.


2021 ◽  
Vol 22 (14) ◽  
pp. 7594
Author(s):  
Rupesh Paudel ◽  
Lorenza Fusi ◽  
Marc Schmidt

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.


Nature ◽  
2016 ◽  
Vol 535 (7612) ◽  
pp. 363-365 ◽  
Author(s):  
Katey Walter Anthony ◽  
Sally MacIntyre
Keyword(s):  

Ethnicities ◽  
2021 ◽  
pp. 146879682199990
Author(s):  
Sagnik Dutta

This article is an ethnographic exploration of a women’s sharia court in Mumbai, a part of a network of such courts run by women qazi (Islamic judges) established across India by members of an Islamic feminist movement called the Bharatiya Muslim Mahila Andolan (Indian Muslim Women’s Movement). Building upon observations of adjudication, counselling, and mediation offered in cases of divorce and maintenance by the woman qazi (judge), and the claims made by women litigants on the court, this article explores the imaginaries of the heterosexual family and gendered kinship roles that constitute the everyday social life of Islamic feminism. I show how the heterosexual family is conceptualised as a fragile and violent institution, and divorce is considered an escape route from the same. I also trace how gendered kinship roles in the heterosexual conjugal family are overturned as men fail in their conventional roles as providers and women become breadwinners in the family. In tracing the range of negotiations around the gendered family, I argue that the social life of Islamic feminism eludes the discourses and categories of statist legal reform. I contribute to existing scholarship on Islamic feminism by exploring the tension between the institutionalist and everyday aspects of Islamic feminist movements, and by exploring the range of kinship negotiations around the gendered family that take place in the shadow of the rhetoric of ‘law reform’ for Muslim communities in India.


2009 ◽  
Vol 8 (1) ◽  
Author(s):  
Chris Roseveare ◽  

Milestones are often seen as opportunities for reflection and reminiscence. As this edition of the journal coincides with the 10th anniversary of my consultant appointment I hope readers will forgive a couple of paragraphs of self-indulgence. The phrase: ‘Where did all that time go?’ will probably be familiar to physicians at a more advanced stage of their career. With medical students now returning as specialist registrars, and former house officers appearing as consultant colleagues, the passage of time is increasingly apparent. I recently realised that our current third year students were born in the year I clerked my first patient: surprisingly I still remember his name, age and diagnosis, unlike many of those (and all of the students!) who I have seen since. On a more positive note, there have clearly been a lot of changes over these ten years: at the time of my appointment in June 1999 there was just a small handful of ‘acute physicians’ in the UK. SAM meetings attracted barely 100 delegates, despite providing free admission, and most of us had planned our escape route in case the acute medicine concept went ‘belly-up’ before our retirement. Now, with several hundred acute medicine consultants, similar numbers of trainees, and ‘full speciality’ status rapidly approaching, job security should no longer be a major concern. Indeed, the last 12 months has seen a further considerable expansion of the speciality; all of the first cohort of acute medicine trainees in Wessex have secured consultant positions, and I am told that SAM now has close to 700 full members. What the next ten years will bring remains to be seen, but with an ageing population and year-round pressures from rising emergency admissions, acute medicine will surely continue to strengthen. As I indicated last time, an increasing number of research-based submissions will be trickling into the journal over the next few editions. The impact of alcohol on the Health Service is a subject which has been at the top of the political agenda in recent months. So it is timely to include an article highlighting its impact on the Acute Medical intake in a busy Teaching hospital in this edition of the journal. The finding that one-in-five patients admitted to the AMU were considered ‘hazardous’ drinkers will probably come as no surprise to acute physicians working elsewhere in the UK. In fact this figure may have been an under-estimate given that the number of units consumer per week was not documented in 30% of clerking records. The demographic shift away from the stereotype ‘middle-aged male’ drinker is also apparent with large numbers of females aged 40-59 falling into this category. Recent editions of this journal would not seem complete without mention of training in practical procedures. In this issue the SAM trainee representatives have summarised the recent trainee survey in this area, providing some recommendations which will hopefully be incorporated into the new curriculum. Readers who are becoming tired of this subject can be reassured that this should be the final article relating to this for the time being! I hope this edition provides interesting reading and please keep the submissions coming – although the review articles are usually solicited by the editorial team, we will continue to consider any submitted article for publication, provided there is a clear teaching message for those working in the field of Acute Medicine. Any feedback on the articles included in this or previous editions would also be welcome, and may be included in a future ‘viewpoint’ or ‘letters to the editor’ section.


Author(s):  
Ch Venkataramaiah ◽  
G Swathi ◽  
W Rajendra

 The morris water maze (MWM) was developed by morris as a device to investigate spatial learning and memory in laboratory rats. MWM has become one of the most frequently used laboratory tools in behavioral neuroscience. The MWM task has been often used in the validation of rodent models for neurocognitive disorders (e.g., Parkinson, Alzheimer, Epilepsy, and Schizophrenia), and the evaluation of possible neurocognitive treatments. It is also being used to assess the properties of established potential antipsychotics in animal models of Schizophrenia. The MWM task requires rats to find a hidden platform in a large, circular pool of water that is colored opaque with powdered non-fat milk (or) non-toxic tempera paint where they must swim to the hidden platform. Because they are in the opaque water, the animals cannot see the platform and cannot rely on scent to find the escape route. Instead, they must rely on extra-maze cues. The behavior of rat can be evaluated by analyzing the different parameters such as escape latency, swim speed, and path length, and probe trail. The purpose of this review is to briefly describe procedural aspects, interpretational difficulties of data and advantages of MWM. This paradigm has become a benchmark test for learning and memory difficulties in animal models and preclinical research in general.


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