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While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.

One of the problems with the transportation system to tourist locations in the Bandung Regency area is congestion which causes an increase in average daily traffic (LHR) due to the use of private vehicles. If the vehicle's LHR increases, the vehicle speed will be low and the cost of transporting the vehicle to tourist locations will become expensive. This research aims to calculate the BOK for the Bandung Regency tourist area, calculate the BOT for the Bandung Regency tourist area and analyze the influence of the transportation system in the Bandung Regency tourist area. The research method uses quantitative and qualitative research (mix method). From the results of BOK calculations and analysis using the Pacific Consultant International (PCI) method, the total BOK value for working days and holidays for Curug Cinulang is IDR 56,582.00. Tebing Keraton Rp. 79,841.00, and Ranca Upas Rp. 103,366.00. From the results of BOT calculations and analysis using the Pacific Consultant International (PCI) method, the total BOT value for weekdays and holidays for Curug Cinulang is IDR 59,714.00. Tebing Keraton Rp. 50,959.00 and Ranca Upas Rp. 108,137.00. Based on the results of the analysis, It can be seen from the indicators that the obstacles faced in daily activities, especially in traveling, are having to deal with traffic jams which cause low vehicle speeds, wasting a lot of time and fuel on the road, thus disrupting travel activity plans. [ABSTRACT FROM AUTHOR]

This research aims to test and analyze the absolute and conditional convergence of per capita income from 38 districts/cities in East Java with the variables PAD, BOS and BOK during the period 2020 - 2022. According to the Chow, Hausmann test and Lagrange Multiplier, the panel data convergence model estimates using the fixed effect model method. Results show that in the districts/cities and observation period, divergent conditions occurred. Also, conditional variables did not have a significant influence on the growth of per capita income. This condition can occur because capital and technology are distributed unevenly between districts/cities. The implication of this research is to improve the allocation and distribution of the government budget, especially those related to School Operational Assistance (BOS) and Health Operational Assistance (BOK).

The Bcl-2 family controls apoptosis by direct interactions of pro- and anti-apoptotic proteins. The principle mechanism is binding of the BH3 domain of pro-apoptotic proteins to the hydrophobic groove of anti-apoptotic siblings, which is therapeutically exploited by approved BH3-mimetic anti-cancer drugs. Evidence suggests that also the transmembrane domain (TMD) of Bcl-2 proteins can mediate Bcl-2 interactions. We developed a highly-specific split luciferase assay enabling the analysis of TMD interactions of pore-forming apoptosis effectors BAX, BAK, and BOK with anti-apoptotic Bcl-2 proteins in living cells. We confirm homotypic interaction of the BAX-TMD, but also newly identify interaction of the TMD of anti-apoptotic BCL-2 with the TMD of BOK, a peculiar pro-apoptotic Bcl-2 protein. BOK-TMD and BCL-2-TMD interact at the endoplasmic reticulum. Molecular dynamics simulations confirm dynamic BOK-TMD and BCL-2-TMD dimers and stable heterotetramers. Mutation of BCL-2-TMD at predicted key residues abolishes interaction with BOK-TMD. Also, inhibition of BOK-induced apoptosis by BCL-2 depends specifically on their TMDs. Thus, TMDs of Bcl-2 proteins are a relevant interaction interface for apoptosis regulation and provide a novel potential drug target. Synopsis: The Bcl-2 family proteins BCL-2 and BOK interact via their transmembrane domains (TMDs) at the endoplasmic reticulum (ER). The TMD interaction interface is critical for the inhibition of BOK-induced apoptosis. BOK and BCL-2 directly interact via their C-terminal transmembrane domains in the ER membrane. Molecular-dynamics simulations reveal formation of higher order oligomers and mutation studies verify the relevance of predicted key residues in the BCL-2-TMD and BOK-TMD interaction interface. Inhibition of BOK-induced cell death by BCL-2 depends on TMD interaction thus exemplifying functional impact of TMD interaction on apoptosis regulation. The Bcl-2 family proteins BCL-2 and BOK interact via their transmembrane domains (TMDs) at the endoplasmic reticulum. The TMD interaction interface is critical for the inhibition of BOK-induced apoptosis. [ABSTRACT FROM AUTHOR]

Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.

The outer mitochondrial membrane is a busy place. One essential activity for cellular survival is the regulation of membrane integrity by the BCL‐2 family of proteins. Another critical facet of the outer mitochondrial membrane is its close approximation with the endoplasmic reticulum. These mitochondrial‐associated membranes (MAMs) occupy a significant fraction of the mitochondrial surface and serve as key signaling hubs for multiple cellular processes. Each of these pathways may be considered as forming their own specialized MAM subtype. Interestingly, like membrane permeabilization, most of these pathways play critical roles in regulating cellular survival and death. Recently, the pro‐apoptotic BCL‐2 family member BOK has been found within MAMs where it plays important roles in their structure and function. This has led to a greater appreciation that multiple BCL‐2 family proteins, which are known to participate in numerous functions throughout the cell, also have roles within MAMs. In this review, we evaluate several MAM subsets, their role in cellular homeostasis, and the contribution of BCL‐2 family members to their functions. [ABSTRACT FROM AUTHOR]

The Chirp Spread Spectrum(CSS) based wireless communication has been widely used in Wireless Sensor Network(WSN). These sensors generally have slow speed, and is becoming more demand for higher data rate. However, due to the low transmission rate of CSS, there are still many problems to be studied. A new modulation method based on the linear chirps is introduced in this paper. Unlike the BOK(Binary Orthogonal Keying) and DM(Direct Modulation) methods, this modulation technique is to implant Doppler frequency shift into the linear chirps. M-ary modulation is realized in a single pulse by this proposed modulation technique. Demodulation is accomplished by calculating the position of the compress pulse peak within the pulse duration, or by using different reference chirp signals in the matching filter. [ABSTRACT FROM AUTHOR]

The article describes the basic principles of the development and architecture of educational and methodological material in the form of a guide for the development of educational programs for training highly qualified professional personnel in cybersecurity (information security). Such guidance in foreign sources is called a curriculum. As in any curriculum, the main content of this manual is the definition of the cybersecurity body of knowledge (CBK) in the form of a multi-level hierarchical structure of didactic units that determine the content of training. In addition, the manual includes the definition of the minimum required amount of knowledge (core of the CBK) for educational programs in cybersecurity, a description of the set of expected characteristics of graduates and learning outcomes, recommendations for practice-oriented training of students, a system of didactic parameters that determine the recommended hourly workload when studying individual elements of the CBK and the level of knowledge transfer in the development of the required skills and other materials. This guide is developed on the basis of the Cybersecurity Skills Model described in the authors' previous article "The Cybersecurity Skills Model 2020". It can serve as a methodological basis for the development of educational programs on cybersecurity at all levels: bachelor's, specialist's, master's. The guide can also be used in the development of continuing education programs, individual curricula and professional self-study programs related to cybersecurity.

While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction. [ABSTRACT FROM AUTHOR]

Regulation of cell life and death by members of the BCL-2 family of proteins occurs at the mitochondria. Large portions of the mitochondria’s outer membrane are found in tight approximation with the endoplasmic reticulum (ER), known as mitochondria-associated membranes (MAMs) or mitochondria-ER contact sites (MERCs). We recently reported that BOK is present within MAMs where it regulates Ca2+ transfer from the ER to the mitochondria, appropriate MAM components and MERC structure, and apoptosis.

Cerebral ischemia/reperfusion (I/R) can lead to serious brain function impairments. Long noncoding RNA (lncRNA) CCAAT enhancer binding protein a antisense RNA 1 (CEBPA-AS1) was shown to be upregulated in human ischemic stroke. This study investigated the function and mechanism of CEBPA-AS1 in I/R. An oxygen-glucose deprivation/reperfusion (OGD/R) model was used to induce I/R injury in SH-SY5Y cells in vitro. RT-qPCR examined the expression of CEBPA-AS1, microRNA 24-3p (miR-24-3p), and Bcl-2-related ovarian killer (Bok). The cell viability, apoptosis, oxidative stress in OGD/R treated cells were detected using CCK-8, flow cytometry, Western blotting, and enzyme-linked immunosorbent assays. The relationship among genes was tested by RNA pulldown and luciferase reporter assays. We found that OGD/R upregulated CEBPA-AS1 expression in SH-SY5Y cells. Functionally, CEBPA-AS1 depletion ameliorated OGD/R-induced apoptosis and oxidative stress in SH-SY5Y cells by reducing reactive oxygen species production and superoxide dismutase and glutathione. Mechanistic investigations indicated that CEBPA-AS1 acts as a sponge for miR-24-3p, and miR-24-3p binds to BOK. Moreover, miR-24-3p upregulation or BOK downregulation antagonized the protective role of CEBPA-AS1 depletion in SH-SY5Y cells exposed to OGD/R. Overall, downregulation of CEBPA-AS1 exerts protective functions against OGD/R-induced injury by targeting the miR-24-3p/BOK axis. [ABSTRACT FROM AUTHOR]

Summary: Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok−/− cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis.

Apoptotic cells are commonly observed in a broad range of tissues during mammalian embryonic and fetal development. Specific requirements and functions of programmed cell death were inferred from early observations. These inferences did not hold up to functional proof for a requirement of apoptosis for normal tissue development in all cases. In this review, we summarize how the appraisal of the importance of developmental apoptosis has changed over the years, in particular with detailed functional assessment, such as by using gene-targeted mice lacking essential initiators or mediators of apoptosis. In recent years, the essentials of developmental apoptosis have emerged. We hypothesize that apoptosis is predominantly required to balance cell proliferation. The two interdependent processes—cell proliferation and apoptosis—together more powerfully regulate tissue growth than does each process alone. We proposed that this ensures that tissues and cell populations attain the appropriate size that allows fusion in the body midline and retain the size of cavities once formed. In addition, a limited number of tissues, albeit not all previously proposed, rely on apoptosis for remodeling, chiefly aortic arch remodeling, elimination of supernumerary neurons, removal of vaginal septa, and removal of interdigital webs in the formation of hands and feet.

Myeloid cell leukemia 1 (MCL1) gene amplification occurs in a wide range of human cancers and protein overexpression associates with malignant cell growth and evasion of apoptosis. We recently reported that disrupting the interaction between the transmembrane domains of MCL1 and BCL-2 related ovarian killer (BOK) induces cell death, thereby suggesting a new target site for anti-tumorigenic strategies.

BCL-2–related ovarian killer (BOK) is—despite its identification over 20 years ago—an incompletely understood member of the BCL-2 family. BCL-2 family proteins are best known for their critical role in the regulation of mitochondrial outer membrane permeabilization during the intrinsic apoptotic pathway. Based on sequence and structural similarities to BAX and BAK, BOK is grouped with these “killers” within the effector subgroup of the family. However, the mechanism of how exactly BOK exerts apoptosis is not clear and controversially discussed. Furthermore, and in accordance with reports on several other BCL-2 family members, BOK seems to be involved in the regulation of a variety of other, “apoptosis-independent” cellular functions, including the unfolded protein response, cellular proliferation, metabolism, and autophagy. Of note, compared with other proapoptotic BCL-2 family members, BOK levels are often reduced in cancer by various means, and there is increasing evidence for BOK modulating tumorigenesis. In this review, we summarize and discuss apoptotic- and non–apoptotic-related functions of BOK, its regulation as well as its physiological and pathophysiological roles.

The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions. [ABSTRACT FROM AUTHOR]

Professor Elms' "how to get to" various items mentioned in the proposed BOK Framework could be an overlay on the BOK Framework. Keywords: Model; system; design; environment; terminology; BOK EN Model system design environment terminology BOK 276 278 3 12/17/21 20211201 NES 211201 I read Professor Elms' contribution to the Special Issue (Elms, [4]) several times. The "how to get to" each of the items in the BOK Framework needs developing in the proposed BOK Framework; the BOK Framework was deliberately written without detailed specifics in order to highlight the bones of a BOK. [Extracted from the article]

Cell death is an essential physiological process required for the proper development and function of the human placenta. Although the mouse is a commonly used animal model for development studies, little is known about the extent and distribution of cell death in the mouse placenta throughout development and its physiological relevance. In the present study, we report the results of a systematic and quantitative assessment of cell death patterns in the placentae of two strains of laboratory mice commonly used for developmental studies—ICR and C57Bl/6. TUNEL staining revealed that ICR and C57Bl/6 placentae exhibited similar cell death patterns to those reported in human placentae during pregnancy, with comparatively infrequent death observed during early gestation, which increased and became more organized towards term. Interestingly, when comparing strain differences, increased cell death was observed in almost all regions of the inbred C57Bl/6 placentae compared to the outbred ICR strain. Finally, since Bcl-2 ovarian killer (Bok) has been reported to be a key player in human placental cell death, we examined its expression in murine placentae throughout gestation. Bok protein expression was observed in all placental regions and increased towards term in both strains. The results of this study indicate that although strain-specific differences in placental cell death exist, the overall rates and patterns of cell death during murine placentation parallel those previously described in humans. Thus, the murine placenta is a useful model to investigate molecular pathways involved in cell death signaling during human placentation. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by cytopenia and intramedullary apoptosis. BCL-2 Ovarian Killer (BOK) is a pro-apoptotic member of the BCL-2 family of proteins which, when stabilized from endoplasmic reticulum-associated degradation (ERAD), induces apoptosis in response to ER stress. Although ER stress appropriately activates the unfolded protein response (UPR) in BOK-disrupted cells, the downstream effector signaling that includes ATF4 is defective. We used Nup98-HoxD13 (NHD13) transgenic mice to evaluate the consequences of BOK loss on hematopoiesis and leukemogenesis. Acute myeloid leukemia developed in 36.7% of NHD13 mice with a Bok gene knockout between the age of 8 and 13 months and presented a similar overall survival to the NHD13 mice. The loss of BOK exacerbated anemia in NHD13 mice, and NHD13/BOK-deficient mice exhibited significantly lower hemoglobin, lower mean cell hemoglobin concentration, and higher mean cell volume than NHD13 mice. Hematopoietic progenitor cell assays revealed a decreased amount of erythroid progenitor stem cells (BFU-E) in the bone marrow of NHD13-transgenic/BOK-deficient mice. RT-qPCR analysis demonstrated decreased mean value of ATF4 in the erythroid progenitors of NHD13 and NHD13/BOK-deficient mice. Our results suggest that in addition to induction of apoptosis in response to ER stress, BOK may regulate erythropoiesis when certain erythroid progenitors experience cell stress. [ABSTRACT FROM AUTHOR]

BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers. [ABSTRACT FROM AUTHOR]

Regulation of cell life and death by members of the BCL-2 family of proteins occurs at the mitochondria. Large portions of the mitochondria's outer membrane are found in tight approximation with the endoplasmic reticulum (ER), known as mitochondria-associated membranes (MAMs) or mitochondria-ER contact sites (MERCs). We recently reported that BOK is present within MAMs where it regulates Ca2+ transfer from the ER to the mitochondria, appropriate MAM components and MERC structure, and apoptosis. [ABSTRACT FROM AUTHOR]

BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.

Myeloid cell leukemia 1 (MCL1) gene amplification occurs in a wide range of human cancers and protein overexpression associates with malignant cell growth and evasion of apoptosis. We recently reported that disrupting the interaction between the transmembrane domains of MCL1 and BCL-2 related ovarian killer (BOK) induces cell death, thereby suggesting a new target site for anti-tumorigenic strategies. [ABSTRACT FROM AUTHOR]

Many people related to ICA have over the years been engaged in the creation of Cartographic Body of Knowledge (CartoBoK). Central persons as Lynn Usery, Georg Gartner, David Fairbairn and Harold Mollering (Fairbairn, 2018; Moellering, 2019) has been involved in this work in various occasions. There is also a section for Cartography and visualization in the GIS&T Body of Knowledge, established by the University Consortium for Geographic Information Science (GIS&T BoK, 2016). [ABSTRACT FROM AUTHOR]

In Abram Brummett and Erica K. Salter's excellent paper, "Mapping the Moral Terrain of Clinical Deception," they rightly note that it is sometimes ethically appropriate for health care professionals to deceive patients and families. However, they also note that because doing so violates a prima facie duty of honesty, the ethical burden of proof falls upon the deceiver. Hence, they also provide a sophisticated framework for determining whether any given case is warranted. I applaud their overall approach but also critique some of their claims, in particular, their conclusion that lies of commission require greater justification than those of omission and their conflation of the principles of beneficence and nonmaleficence. I also urge them to give greater attention to how power asymmetries should be accounted for and to the impact such deceptive choices might have on the clinician's character. [ABSTRACT FROM AUTHOR]

As the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small-cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues ( p < 0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two ( p = 0.004, n = 35) and three ( p = 0.031, n = 39) as well as in tumors with metastases to hilar (pN1) ( p = 0.047, n = 31) and mediastinal/subcarinal lymph nodes (pN2) ( p = 0.021, n = 18) as opposed to grade one tumors ( p = 0.688, n = 7) and tumors without lymph node metastases ( p = 0.112, n = 51). Importantly, in lymph node-positive patients, BOK expression greater than the median value was associated with longer survival ( p = 0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients. [ABSTRACT FROM AUTHOR]

Neuronal cell death is often triggered by events that involve intracellular increases in Ca 2+ . Under resting conditions, the intracellular Ca 2+ concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca 2+ overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca 2+ -dependent cell death. Excessive Ca 2+ entry though glutamate receptors (excitotoxicity) has been implicated in several neurologic and chronic neurodegenerative diseases, including ischemic stroke, epilepsy, and Alzheimer's disease. Recent evidence has revealed that excitotoxic cell death is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins. Bcl-2 proteins, comprising of both pro-apoptotic and anti-apoptotic members, have been shown to not only mediate the intrinsic apoptosis pathway by controlling mitochondrial outer membrane (MOM) integrity, but to also control neuronal Ca 2+ homeostasis and energetics. In this review, the role of Bcl-2 family proteins in the regulation of apoptosis, their expression in the central nervous system and how they control Ca 2+ -dependent neuronal injury are summarized. We review the current knowledge on Bcl-2 family proteins in the regulation of mitochondrial function and bioenergetics, including the fusion and fission machinery, and their role in Ca 2+ homeostasis regulation at the mitochondria and ER. Specifically, we discuss how the ‘pro-apoptotic’ Bcl-2 family proteins, Bax and Bok, physiologically expressed in the nervous system, regulate such ‘non-apoptotic/daytime’ functions. [ABSTRACT FROM AUTHOR]

The BCL-2 family members are key regulators of the intrinsic apoptotic pathway, which is defined by permeabilization of the mitochondrial outer membrane by members of the BAX-like subfamily. BOK is classified as a BAX-like protein; however, its (patho-)physiological role remains largely unclear. We therefore assessed the membrane permeabilization potential of C-terminally truncated recombinant BOK, BOK∆C. We show that BOK∆C can permeabilize liposomes mimicking the composition of mitochondrial outer membrane, but not of endoplasmic reticulum, forming large and stable pores over time. Importantly, pore formation was enhanced by the presence of cBID and refractory to the addition of antiapoptotic BCL- XL. However, isolated mitochondria from Bax −/− Bak −/− cells were resistant to BOK-induced cytochrome c release, even in the presence of cBID. Taken together, we show that BOK∆C can permeabilize liposomes, and cooperate with cBID, but its role in directly mediating mitochondrial permeabilization is unclear and may underlie a yet to be determined negative regulation. [ABSTRACT FROM AUTHOR]

The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak (also known as BAK1) are considered the gatekeepers of the intrinsic pathway of apoptosis by triggering the mitochondrial release of cytochrome c. The role of the third Bax- and Bak-homologous multidomain protein Bok, however, is still unresolved. As cells doubly deficient for Bax and Bak are largely resistant to various apoptotic stimuli, it has been proposed that Bok is either dispensable for apoptosis or that its role is dependent on Bax and Bak. Here, we demonstrate, in several cell systems, that Bok efficiently induces cytochrome c release and apoptosis even in the complete absence of both Bak and Bax. Moreover, modulation of endogenous Bok levels affects the apoptosis response. By RNA interference and targeted deletion of the Bok gene, we demonstrate that Bok can significantly influence the apoptotic response to chemotherapeutic drugs in ovarian carcinoma cells. Hence, our results not only establish Bok as a Bak- and Bax-independent apoptosis inducer, but also suggest a potential impact of Bok expression in ovarian cancer therapy. [ABSTRACT FROM AUTHOR]

Apoptosis plays vital roles in many physiological process and immune response. BOK is one of the central regulators in apoptosis. In this study, a new BOK homolog (Ec-BOK) was cloned and characterized from Orange-spotted grouper, Epinephelus coioides . Ec-BOK encoded a 210 amino acid peptides which shared 97% identity to Stegastes partitus BOK protein, contained four BH domains and one transmembrane region. Ec-BOK widely expressed in all analyzed tissues with the higher expressions in kidney and spleen. Its expression level was up-regulated after SGIV infection in vitro . Further analysis revealed that overexpression of Ec-BOK inhibited viral genes transcriptions and virus replication in fish cell. Our findings suggested that Ec-BOK might play a role in the immune response against virus. [ABSTRACT FROM AUTHOR]

Periodic updates are required to ensure the ASQ Certified Software Quality Engineer (CSQE) program continues to reflect accepted professional practices. An individual receives the CSQE designation as a result of successfully completing the certification exam. In turn, the exam is built on the content described in the current CSQE Body of Knowledge (BoK). This BoK has just undergone its latest revision. This article describes the revision process, starting with a job analysis survey. After survey results were used to modify the BoK, corresponding changes were made to the question bank for the certification exam. Finally, an updated draft exam was produced and evaluated. Specific changes that were made to the BoK are available online and will be discussed in a subsequent article. [ABSTRACT FROM AUTHOR]

Age related decline in reproductive performance in women is well documented and apoptosis has been considered as one of the reasons for the decline of primordial follicle reserve. Recently we observed a decline in the efficiency of DNA repair ability in aged rat primordial follicles as demonstrated by decreased mRNA levels of DNA repair genesBRCA1andH2AX. In the present study, a two-dimensional electrophoresis (2DE) proteomic approach was employed to identify differentially expressed proteins in primordial follicles isolated from ovaries of immature (∼20 days) and aged (∼400–450 days) rats. Using MALDI-TOF/TOF MS, we identified 13 differentially expressed proteins (p < 0.05) which included seven up-regulated and six down-regulated proteins in aged primordial follicles. These proteins are involved in a wide range of biological functions including apoptosis, DNA repair, and the immune system. Interestingly, the differentially expressed proteins such as FIGNL1 (DNA repair) and BOK (apoptotic protein) have not been previously reported in the rat primordial follicles and these proteins can be related to some common features of ovarian aging such as loss of follicle reserve and genome integrity. The quantitative differences of two important proteins BOK and FIGNL1 observed by the proteomic analysis were correlated with the transcript levels, as determined by semi-quantitative RT-PCR. Our results improve the current knowledge about protein factors associated with molecular changes in rat primordial follicles as a function of aging and our understanding of the proteomic processes involved in degenerative changes observed in aging primordial follicles. [ABSTRACT FROM PUBLISHER]