Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynein prevents erroneous kinetochore-microtubule attachments in mitosis

Equal distribution of the genetic material during cell division relies on efficient congression of chromosomes to the metaphase plate. Prior to their alignment, the Dynein motor recruited to kinetochores transports a fraction of laterally-attached chromosomes along microtubules toward the spindle poles. By doing that, Dynein not only contributes to chromosome movements, but also prevents premature stabilization of end-on kinetochore-microtubule attachments. This is achieved by 2 parallel mechanisms: 1) Dynein-mediated poleward movement of chromosomes counteracts opposite polar-ejection forces (PEFs) on chromosome arms by the microtubule plus-end-directed motors chromokinesins. Otherwise, they could stabilize erroneous syntelic kinetochore-microtubule attachments and lead to the random ejection of chromosomes away from the spindle poles; and 2) By transporting chromosomes to the spindle poles, Dynein brings the former to the zone of highest Aurora A kinase activity, further destabilizing kinetochore-microtubule attachments. Thus, Dynein plays an important role in keeping chromosome segregation error-free by preventing premature stabilization of kinetochore-microtubule attachments near the spindle poles.
The Functional Exercise Capacity Is Associated With Global Functioning in People With Bipolar Disorder

Abstract The aim of the current study was to determine whether the Global Assessment of Functioning (GAF) score is associated with the functional exercise capacity among in- and outpatients with bipolar disorder. Sixty-five (36♀) persons with bipolar disorder performed a 6-minute walk test (6MWT) and were assessed with the GAF, Quick Inventory of Depressive Symptomatology Self Report (QIDS), and the International Physical Activity Questionnaire (IPAQ). The mean GAF-score was 55.0 ± 15.0, whereas the mean distance achieved on the 6MWT was 615.6 ± 118.6 m. There was a positive association between the GAF score and 6MWT score (r = 0.60, p < 0.001). A backward regression analysis demonstrated that an inpatient status, illness duration (16.1 ± 10.7 years), and the QIDS score (7.7 ± 5.7) explained 72.4% of the GAF-score variance. The GAF, QIDS score, and age explained 74.1% of the 6MWT-score variance. Our results indicate that a bidirectional relationship is evident between the exercise capacity and global functioning among people with bipolar disorder.
Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity–dependent suicidal inhibition of its polo-box domain

Polo-like kinase 1 (Plk1) plays a critical role in proper M-phase progression and cell proliferation. Plk1 is overexpressed in a broad spectrum of human cancers and is considered an attractive anticancer drug target. Although a large number of inhibitors targeting the catalytic domain of Plk1 have been developed, these inhibitors commonly exhibit a substantial level of cross-reactivity with other structurally related kinases, thus narrowing their applicable dose for patient treatment. Plk1 contains a C-terminal polo-box domain (PBD) that is essentially required for interacting with its binding targets. However, largely due to the lack of both specific and membrane-permeable inhibitors, whether PBD serves as an alternative target for the development of anticancer therapeutics has not been rigorously examined. Here, we used an intracellularly expressed 29-mer-long PBIP1-derived peptide (i.e., PBIPtide), which can be converted into a “suicidal” PBD inhibitor via Plk1-dependent self-priming and binding. Using this highly specific and potent system, we showed that Plk1 PBD inhibition alone is sufficient for inducing mitotic arrest and apoptotic cell death in cancer cells but not in normal cells, and that cancer cell–selective killing can occur regardless of the presence or absence of oncogenic RAS mutation. Intriguingly, PBD inhibition also effectively prevented anchorage-independent growth of malignant cancer cells. Thus, targeting PBD represents an appealing strategy for anti-Plk1 inhibitor development. Additionally, PBD inhibition–induced cancer cell–selective killing may not simply stem from activated RAS alone but, rather, from multiple altered biochemical and physiological mechanisms, which may have collectively contributed to Plk1 addiction in cancer cells.
Avaliação da qualidade de vida em pacientes com diabetes mellitus e pé ulcerado

BACKGROUND: Diabetic foot is considered as one of the most devastating chronic complications of diabetes mellitus due to the large number of cases that eventually require amputation. In the present study, we aimed to assess the quality of life of patients with diabetes and foot ulcers compared to that of patients with diabetes but without foot ulcers. METHODS: An analytical, cross-sectional, controlled, and comparative study of patients who visited 2 wound clinics in Sao Paulo was performed. Fifty patients with diabetes mellitus but without foot ulcers were selected as the control group and 50 patients with diabetes and foot ulcers were selected as the study group. The Short Form-36 Health Survey (SF-36) questionnaire was used to assess the quality of life. Patients were included consecutively in the same order that they visited the clinic. RESULTS: The mean SF-36 score was 69.38 ± 21.90 in the control group and 30.34 ± 14.45 in the study group (P < 0.001). Mean scores across all SF-36 domains were lower in the study group than in the control group (P < 0.001). CONCLUSIONS: Patients with diabetes and foot ulcers experience changes in the quality of life in the physical, social, and psychoemotional domains.
The Effect of Age, Race, and Sex on Social Cognitive Performance in Individuals With Schizophrenia

Abstract Age, race, and sex are linked to social cognitive performance among healthy individuals, but whether similar effects are evident in schizophrenia is unknown. Data from 170 individuals with schizophrenia or schizoaffective disorder and 98 healthy controls were used to examine relations between these demographic factors and performance across multiple domains and measures of social cognition. Sex was not related to performance on any domain, but older age was related to poorer emotion recognition from dynamic stimuli in both patients and controls. In patients, older age was also associated with better abilities to decipher hints. Both Caucasian patients and controls performed better than African American individuals on emotion recognition and mental state attribution tasks that use only Caucasian individuals as visual stimuli. Findings suggest rather limited influences of demographic factors but do demonstrate normative age and race effects among patients. Findings also highlight important methodological considerations for measurement of social cognition.
Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans

In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV‐related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real‐time polymerase chain reaction. Liver samples from patients with HBV‐related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA‐HEIH); data were compared with survival data using the Kaplan‐Meier method and compared between groups by the log‐rank test. The effects of lncRNA‐HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA‐HEIH in HBV‐related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA‐HEIH plays a key role in G0/G1 arrest, and further demonstrated that lncRNA‐HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. Conclusions: Together, these results indicate that lncRNA‐HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression. (HEPATOLOGY 2011
Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4

ABSTRACT We found that inhibitors of mitochondrial respiratory chain complexes III (myxothiazol) and I (piericidin A) in some epithelial carcinoma cell lines induce transcription of the p53-responsive SESN2 gene that plays an important role in stress response and homeostatic regulation. However, the effect did not depend on p53 because i) there was no induction of p53 after the treatment with piericidin A; ii) after the treatment with myxothiazol the peak of SESN2 gene upregulation occurred as early as 5h, before the onset of p53 activation (13h); iii) a supplementation with uridine that abolishes the p53 activation in response to myxothiazol did not abrogate the induction of SESN2 transcripts; iv) in the p53 negative HCT116 p53 -/- cells SESN2 transcription could be also induced by myxothiazol. In response to the respiratory chain inhibitors we observed an induction of ATF4, the key transcription factor of the integrated stress response (ISR). We found that the induction of SESN2 transcripts could be prevented by the ISR inhibitory small molecule ISRIB. Also, by inhibiting or overexpressing ATF4 with specific shRNA or ATF4-expressing constructs, respectively, we have confirmed the role of ATF4 in the SESN2 gene upregulation induced by mitochondrial dysfunction. At a distance of 228 bp upstream from the SESN2 transcription start site we found a candidate sequence for the ATF4 binding site and confirmed its requirement for the induction of SESN2 in luciferase reporter experiments. We suggest that the upregulation of SESN2 by mitochondrial dysfunction provides a homeostatic feedback that attenuates biosynthetic processes during temporal losses of energy supply from mitochondria thereby assisting better adaptation and viability of cells in hostile environments.
Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor

Increased vascular permeability and excessive neovas-cularization are the hallmarks of endothelial dysfunction, which can lead to diabetic macular edema and proliferative diabetic retinopathy in the eye. Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular tissues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms α, βII, and δ and > threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly by the β-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC β-isoform-selective inhibitor that did not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascular permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC β-isoform-selective inhibitors may prove efficacious for the treatment of VEGF-asso-ciated ocular disorders such as diabetic retinopathy.
Death by Suicide Within 1 Week of Hospital Discharge: A Retrospective Study of Root Cause Analysis Reports

Abstract There is a high risk for death by suicide after discharge from an inpatient mental health unit. To better understand system and organizational factors associated with postdischarge suicide, we reviewed root cause analysis reports of suicide within 7 days of discharge from across all Veterans Health Administration inpatient mental health units between 2002 and 2015. There were 141 reports of suicide within 7 days of discharge, and a large proportion (43.3%, n = 61) followed an unplanned discharge. Root causes fell into three major themes including challenges for clinicians and patients after the established process of care, awareness and communication of suicide risk, and flaws in the established process of care. Flaws in the design and execution of processes of care as well as deficits in communication may contribute to postdischarge suicide. Inpatient teams should be aware of the potentially heightened risk for suicide among patients with unplanned discharges.
A survey of bacteriological quality of drinking water in North Gondar

Background: The high prevalence of diarrheal disease among children and infants can be traced to the use of unsafe water and unhygienic practices. The over all concept adopted for microbiological quality is that no water intended for human consumption shall contain E. coli in 100 ml sample. But, a 1-10 E.coli count per 100 ml is acceptable that needs regular sanitary checks for un chlorinated water. Objectives: To assess the extent of bacterial contamination among protected and unprotected water sources. Methods: A cross-sectional study on drinking water quality in North Gondar region was conducted from May to June 2000. Water samples were taken for bacteriological analysis. Results: Analysis of protected springs, protected wells and water lines showed that 35.7%, 28.6% and 50% of the water samples had E. coli, respectively. On the other hand, 50% of the unprotected wells and springs had a fecal coliform count of 180 and above. Conclusions: The majority of the drinking water sources are either of unacceptable quality or grossly polluted. Regular quality control mechanisms need to be in place to ensure safety of drinking water. [Ethiop.J.Health Dev. 2004;18(2):112-115]
The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment

ABSTRACT Faithful chromosome segregation relies on dynamic interactions between spindle microtubules and chromosomes. Especially, all chromosomes must be aligned at the equator of the spindle to establish bi-orientation before they start to segregate. The spindle assembly checkpoint (SAC) monitors this process, inhibiting chromosome segregation until all chromosomes achieve bi-orientation. The original concept of ‘checkpoints’ was proposed as an external surveillance system that does not play an active role in the process it monitors. However, accumulating evidence from recent studies suggests that SAC components do play an active role in chromosome bi-orientation. In this review, we highlight a novel Mad1 role in chromosome alignment, which is the first conserved mechanism that links the SAC and kinesin-mediated chromosome gliding.
BRCA1-hapoinsufficiency: Unraveling the molecular and cellular basis for tissue-specific cancer

abstract Over the past 20 years tremendous progress has been made in understanding the function of BRCA1 gene products. Yet one question still remains: why is mutation of BRCA1 typically associated with preferential development of breast and ovarian cancers and not tumors in other tissues? Here we discuss recent evidence documenting the effect of BRCA1-haploinsufficiency in different cells and tissues and synthesize a model for how mutations in a single BRCA1 allele in human cells might preferentially confer increased cancer risk in breast epithelial cells.
Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

ABSTRACT We demonstrate in the present study that young host mice rejuvenate aged hair follicles after transplantation. Young mice promote the hair shaft growth of transplanted old hair follicles, as well as young follicles, in contrast to old host mice, which did not support hair-shaft growth from transplanted old or young follicles. Nestin-expressing hair follicle-associated pluripotent (HAP) stem cells of transplanted old and young hair follicles remained active in young host nude mice. In contrast, the nestin-expressing HAP stem cells in young and old hair follicles transplanted to old nude mice were not as active as in young nude host mice. The present study shows that transplanted old hair follicles were rejuvenated by young host mice, suggesting that aging may be reversible.
Dissociative Disorders and Suicidality in Psychiatric Outpatients

Although it is common for patients with dissociative disorders to report a history of suicide attempts, there is very little data systematically comparing suicidality in patients with dissociative disorders versus patients without these disorders. The subjects in our study were 231 patients consecutively admitted to an inner-city, hospital-based outpatient psychiatric clinic. Eighty-two of these patients completed structured interviews for dissociative disorders, borderline personality disorder, and trauma history (dissociative disorders interview schedule) and for posttraumatic stress disorder and substance abuse (Structured Clinical Interview for DSM-IV). Patients receiving a dissociative disorder diagnosis were compared with nondissociative patients on measures of self-harm and suicidality. Presence of a dissociative disorder was strongly associated with all measures of self-harm and suicidality. When we focused on patients with a history of multiple suicide attempts, significant associations were found between several diagnoses (dissociative disorder; borderline personality disorder; posttraumatic stress disorder; alcohol abuse/dependence) and multiple suicide attempter status. When these diagnoses were entered in a logistic regression, a highly significant association remained for dissociative diagnosis and multiple suicide attempter status (odds ratio, 15.09; 95% confidence interval, 2.67–85.32; p = 0.002). Dissociative disorders are commonly overlooked in studies of suicidality, but in this population they were the strongest predictor of multiple suicide attempter status.
Toll‐like receptor 2–mediated innate immune response in human nonparenchymal liver cells toward adeno‐associated viral vectors

Adeno‐associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic T cells correlates with liver inflammation and loss of transduced hepatocytes. Because adaptive immune responses are a consequence of recognition by the innate immune system, we aimed to characterize cell autonomous immune responses elicited by rAAV in primary human hepatocytes and nonparenchymal liver cells. Surprisingly, Kupffer cells, but also liver sinusoidal endothelial cells, mounted responses to rAAV, whereas neither rAAV2 nor rAAV8 were recognized by hepatocytes. Viral capsids were sensed at the cell surface as pathogen‐associated molecular patterns by Toll‐like receptor 2. In contrast to the Toll‐like receptor 9–mediated recognition observed in plasmacytoid dendritic cells, immune recognition of rAAV in primary human liver cells did not induce a type I interferon response, but up‐regulated inflammatory cytokines through activation of nuclear factor κB. Conclusion: Using primary human liver cells, we identified a novel mechanism of rAAV recognition in the liver, demonstrating that alternative means of sensing rAAV particles have evolved. Minimizing this recognition will be key to improving rAAV‐mediated gene transfer and reducing side effects in clinical trials due to immune responses against rAAV. (Hepatology 2012;55:287–297)
Autophagy regulates biliary differentiation of hepatic progenitor cells through Notch1 signaling pathway

ABSTRACT Autophagy plays important roles in self-renewal and differentiation of stem cells. Hepatic progenitor cells (HPCs) are thought to have the ability of self-renewal as well as possess a bipotential capacity, which allows them to differentiate into both hepatocytes and bile ductular cells. However, how autophagy contributes to self-renewal and differentiation of hepatic progenitor cells is not well understood. In this study, we use a well-established rat hepatic progenitor cell lines called WB-F344, which is treated with 3.75 mM sodium butyrate (SB) to promote the differentiation of WB-F344 along the biliary phenotype. We found that autophagy was decreased in the early stage of biliary differentiation, and maintained a low level at the late stage. Activation of autophagy by rapamycin or starvation suppressed the biliary differentiation of WB-F344. Further study reported that autophagy inhibited Notch1 signaling pathway, which contributed to biliary differentiation and morphogenesis. In conclusions, autophagy regulates biliary differentiation of hepatic progenitor cells through Notch1 signaling pathway.
Glucocorticoids increase interleukin‐6–dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor

Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well‐documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross‐talk between glucocorticoids and interleukin‐6 (IL‐6) in the liver. IL‐6 exerts pro‐inflammatory as well as anti‐inflammatory properties and is a main inducer of the acute‐phase response. The balance between the proinflammatory and anti‐inflammatory activities of IL‐6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well‐known feedback inhibitor of IL‐6 signaling. Here, it is demonstrated that glucocorticoids enhance IL‐6–dependent γ‐fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down‐regulation of SOCS3 protein expression. Consequently, in SOCS3‐deficient cells glucocorticoids do not affect IL‐6–induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL‐6–dependent γ‐fibrinogen expression is not influenced by glucocorticoid treatment. Conclusion: Glucocorticoids interfere with IL‐6–induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute‐phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute‐phase gene induction. (HEPATOLOGY 2012;55:256–266)