Killing Me Softly: Connotations to Unfolded Protein Response and Oxidative Stress in Alzheimer’s Disease

This review is focused on the possible causes of mitochondrial dysfunction in AD, underlying molecular mechanisms of this malfunction, possible causes and known consequences of APP, Aβ, and hyperphosphorylated tau presence in mitochondria, and the contribution of altered lipid metabolism (nonsterol isoprenoids) to pathological processes leading to increased formation and accumulation of the aforementioned hallmarks of AD. Abnormal protein folding and unfolded protein response seem to be the outcomes of impaired glycosylation due to metabolic disturbances in geranylgeraniol intermediary metabolism. The origin and consecutive fate of APP, Aβ, and tau are emphasized on intracellular trafficking apparently influenced by inaccurate posttranslational modifications. We hypothesize that incorrect intracellular processing of APP determines protein translocation to mitochondria in AD. Similarly, without obvious reasons, the passage of Aβ and tau to mitochondria is observed. APP targeted to mitochondria blocks the activity of protein translocase complex resulting in poor import of proteins central to oxidative phosphorylation. Besides, APP, Aβ, and neurofibrillary tangles of tau directly or indirectly impair mitochondrial biochemistry and bioenergetics, with concomitant generation of oxidative/nitrosative stress. Limited protective mechanisms are inadequate to prevent the free radical-mediated lesions. Finally, neuronal loss is observed in AD-affected brains typically by pathologic apoptosis

Nocturnal paroxysmal dystonia – Case report

Nocturnal paroxysmal dystonia describes a syndrome consisting of recurrent motor episodes of dystonic–dyskinetic features arising from non-rapid eye movement (NREM) sleep. In the article, the authors present female case of nocturnal paroxysmal dystonia. The patient has had attacks since her childhood and was eventually diagnosed at the age of 48. Therapy with carbamazepine considerably reduced the frequency and entent of seizures. The present case evidences that nocturnal paroxysmal dystonia still is a diagnostic challenge for clinicians. Especially, we emphasize the importance of polysomnography in the verification of the diagnosis

Assessment of the effectiveness of communication between the participants of a construction project utilizing meta-network theory: a case study

This paper investigates the fact that construction projects, due to their specificity, are complex, temporary and dynamic. Over their course, participants change, successive construction works are done and new information becomes available. This carries over to difficulties in communication. In the literature, numerous studies note the fact that a network-based approach to the analysis and monitoring of communication as a part of complex construction projects is commendable. Relations between agents, knowledge and tasks in the context of communication within a construction project can be visualized in the form of a meta-network, and suitably developed structural measures can be used to analyze them. In this paper, the authors used meta-network theory to analyze relations between project participants, knowledge and tasks in the context of communication within a construction project, on the basis of the construction of a housing estate located in Katowice, Poland. Meta-network structural analysis allowed for a deeper understanding of these relations and the detection of essential information about the level of communication in the project under investigation, which was a basis for further discussion. The authors also stress the benefits from the approach presented and argue that it should be a starting point for effective management in the sphere of communication in construction companies

Heat shock protein A2 is a novel extracellular vesicle-associated protein

70-kDa Heat Shock Proteins (HSPA/HSP70) are chaperones playing a central role in the proteostasis control mechanisms. Their basal expression can be highly elevated as an adaptive response to environmental and pathophysiological stress conditions. HSPA2, one of poorly characterised chaperones of the HSPA/HSP70 family, has recently emerged as epithelial cells differentiation-related factor. It is also commonly expressed in cancer cells, where its functional significance remains unclear. Previously, we have found that proteotoxic stress provokes a decrease in HSPA2 levels in cancer cells. In the present study we found that proteasome inhibition-related loss of HSPA2 from cancer cells neither is related to a block in the gene transcription nor does it relate to increased autophagy-mediated disposals of the protein. Proteotoxic stress stimulated extracellular release of HSPA2 in extracellular vesicles (EVs). Interestingly, EVs containing HSPA2 are also released by non-stressed cancer and normal cells. In human urinary EVs levels of HSPA2 were correlated with the levels of TSG101, one of the main EVs markers. We conclude that HSPA2 may constitute basic components of EVs. Nevertheless, its specific role in EVs and cell-to-cell communication requires further investigation

The association of maternal gestational diabetes mellitus with autism spectrum disorders in the offspring

Wstęp. Istnieją dane wskazujące na związek między występowaniem cukrzycy przedciążowej u matki a ryzykiem zaburzeń ze spektrum autyzmu (ASD) u dziecka. Mniej jest dostępnych informacji dotyczących wpływu cukrzycy po raz pierwszy rozpoznanej w czasie ciąży (GDM) na ryzyko ASD. Badanie przeprowadzono w celu oceny częstości występowania ASD u dzieci matek, u których rozpoznano GDM. Materiał i metody. Autorzy przeanalizowali dokumentację medyczną pacjentek z GDM (947 kobiet, 1007 dzieci w wieku 4-6 lat) leczonych w Klinice Chorób Metabolicznych Szpitala Uniwersyteckiego w Krakowie w latach 1999-2011. Przeprowadzili również wywiad telefoniczny w celu zebrania danych klinicznych oraz informacji na temat parametrów biochemicznych. Wykonano test istotności, opierając się na rozkładzie dwumianowym prawdopodobieństwa w celu ustalenia, czy częstość występowania ASD u dzieci matek z GDM różniła się od dostępnych danych epidemiologicznych dotyczących ogólnej populacji polskich dzieci w wieku 0-18 lat. Sprawdzono również, czy istnieją inne istotne czynniki różnicujące matki z GDM w zależności od występowania ASD u ich potomstwa. Wyniki. Częstość występowania ASD u dzieci kobiet z GDM uczestniczących w badaniu autorów (8/1007) była wyższa niż w populacji polskich dzieci w wieku 0–18 (17,6/10 000; p = 0,0004). Stwierdzono, że w grupie matek dzieci z ASD przedciążowe mediany wartości wskaźnika BMI (20,862 vs. 23,529), SBP (110 mm Hg vs. 120 mm Hg) i DBP (70 mm Hg vs. 80 mm Hg) były niższe niż w grupie matek, u których dzieci nie rozpoznano ASD (odpowiednio p = 0,0349; p = 0,0149 i p = 0,0306). Urodzeniowa masa ciała dzieci z ASD była istotnie wyższa niż w przypadku dzieci bez ASD (3695 g vs. 3320 g; p = 0,0482). Wnioski. Częstość występowania ASD jest wyższa u dzieci matek z GDM niż w populacji ogólnej. Badanie potencjalnych czynników ryzyka ma podstawowe znaczenie dla lepszego zrozumienia tego zjawiska i ustalenia, jak mu zapobiec.Introduction. Some evidence exists for the association between exposure to pregestational maternal diabetes and risk of autism spectrum disorders (ASD) in offspring. Less information is available on the association of exposure to maternal gestational diabetes mellitus (GDM) with risk of ASD. We aimed to examine the prevalence of ASD disorders in offspring of mothers diagnosed with GDM. Material and methods. We analyzed data gathered from GDM patients (947 women; 1007 children aged 4-16 years) treated at the Department of Metabolic Diseases, University Hospital in Krakow from 1999 to 2011. We conducted a telephone survey to collect clinical information and biochemical parameters. We performed significance test based on the exact binomial probability to assess if the prevalence rate of ASD in offspring of mothers with GDM was different from available epidemiological data for children aged 0–18 years in Poland. We also checked whether there are any significant factors discriminating the mothers and offspring with and without ASD. Results. The prevalence of ASD in the offspring of mothers with GDM in our study (8/1007) was higher than in children aged 0-18 years in Poland (17.6/10000; p = 0.0004). The mothers of children with ASD had median pre-pregnancy BMI (20.862 vs. 23.529), SBP (110 mm Hg vs. 120 mm Hg) and DBP (70 mm Hg vs. 80 mm Hg) lower vs. group without ASD (p = 0.0349; p = 0.0149 and p = 0.0306 respectively). Birth weight of ASD children was significantly higher vs group without ASD (3695 g vs. 3320 g, p = 0.0482). Conclusions. The prevalence of ASD seems to be higher in offspring of mothers with GDM than in the general population. Studying the potential risk factors is crucial for better understanding of this phenomenon and it may be helpful to preventi it

Double thrombolysis in early pregnancy can be safe

W niniejszej pracy przedstawiono przypadek kobiety w ciąży ze zdiagnozowaną masywną zatorowością płucną, która przeszła pomyślnie podwójną trombolizę. Pacjentka w wieku 23 lat w 7. tygodniu trzeciej ciąży została przyjęta na Oddział Intensywnej Opieki Kardiologicznej 2 h po nagłym pojawieniu się bólu w klatce piersiowej i duszności. W wykonanym w trybie pilnym badaniu elektrokardiograficznym stwierdzono tachykardię zatokową z typowym zespołem S1Q3T3 i rsr’ w odprowadzeniu V1. W przezklatkowym badanie echokardiograficznym przeprowadzonym przy przyjęciu wykazano przeciążenie prawej komory. W tomografii komputerowej klatki piersiowej z opcją naczyniową (angio-TK) wykonanej w trybie nagłym uwidoczniono rozległą skrzeplinę w obu tętnicach płucnych, ograniczającą przepływ krwi. Początkowo stosowano heparynę niefrakcjonowaną we wlewie, pod kontrolą czasu częściowej tromboplastyny po aktywacji. Mimo leczenia stan pacjentki pogarszał się, dlatego też zdecydowano o podaniu pełnej dawki alteplazy (10 mg bolus, następnie 90 mg przez kolejne 2 h). Uzyskano istotną poprawę stanu klinicznego chorej. Badanie ultrasonograficzne naczyń miednicy i kończyn dolnych wykazało wrzecionowatego kształtu skrzeplinę w rozwidleniu prawej żyły biodrowej wspólnej i zewnętrznej żyły biodrowej. W 10. dniu hospitalizacji, podczas uruchamiania, wystąpiły u pacjentki objawy wstrząsu. Chora wymagała intubacji dotchawiczej, wentylacji mechanicznej i stosowania wlewu amin katecholowych. Drugi raz zastosowano pełną dawkę alteplazy. Nie zaobserwowano dalszych komplikacji podczas ciąży. Pacjentka urodziła w 38. tygodniu siłami natury zdrowego syna ważącego 3580 g (10 punktów w skali Apgar). Po porodzie zamieniono heparynę drobnocząsteczkową na warfarynę (pod kontrolą INR). Wykazano, że podwójna tromboliza u kobiety we wczesnym okresie ciąży może być bezpieczna zarówno dla matki, jak i dziecka, ale konieczne jest przeprowadzenie badań obejmującym większą grupę chorych.We describe the case of pregnant patient with diagnosed massive pulmonary embolism, who underwent successful double thrombolysis. A 23-year-old woman in the 7th week of her 3rd pregnancy was admitted to the Intensive Cardiac Care Unit 2 h after sudden onset of chest pain and dyspnoea. An immediate electrocardiography showed sinus tachycardia with typical S1Q3T3 pattern and rsr’ complex in lead V1. Transthoracic echocardiography on admission revealed right ventricular strain. We performed emergent computed tomography angiography of the chest, which showed significant thrombus in both pulmonary arteries, resulting in restricted blood flow. The patient was treated with unfractionated heparin infusion, monitored by activated partial thromboplastin time. Because of her deteriorating condition, we administered alteplase (10 mg bolus, then 90 mg over the next 2 h). Ultrasonography examination of her pelvis and lower extremities revealed spindle-shaped thrombus of the right common iliac and external iliac veins. On her 10th day of hospitalisation, during the patient’s mobilisation, she presented with symptoms of shock. She needed endotracheal intubation, mechanical ventilation and vasoconstrictor support. We treated her with a second round of full dose alteplase. No complications further developed for the mother or foetus in the subsequent days. She gave birth to a healthy son weighing 3580 g with Apgar score of 10 points in her 38th week of pregnancy by natural delivery. After delivery we switched low molecular weight heparin to warfarin according to her international normalised ratio. In conclusion, double thrombolysis in early pregnancy proved to be safe for both the mother and child, but additional studies need to be performed

DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation

LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease (PD), with growing importance also for Crohn’s disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status. In this regard, many LRRK2 PD-associated mutants display decreased phosphorylation of the constitutive phosphorylation cluster S910/S935/S955/S973, but the role of these changes in phosphorylation status with respect to LRRK2 physiological functions remains unknown. Here, we propose that the S910/S935/S955/S973 phosphorylation sites act as key regulators of LRRK2-mediated autophagy under both basal and starvation conditions. We show that quadruple LRRK2 phosphomutant cells (4xSA; S910A/S935A/S955A/S973A) have impaired lysosomal functionality and fail to induce and proceed with autophagy during starvation. In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. In explanation, we demonstrate that the autophagy impairment due to the 4xSA LRRK2 phospho-dead mutant is driven by its enhanced LRRK2 kinase activity. We show mechanistically that this involves increased phosphorylation of LRRK2 downstream targets Rab8a and Rab10, as the autophagy impairment in 4xSA LRRK2 cells is counteracted by expression of phosphorylation-deficient mutants T72A Rab8a and T73A Rab10. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology