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For the sake of reproducibility - a technical replicate

by Tumor Necrosis Factor-alpha

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1.
Humanity’s endeavour towards the mitigation of the consequences of deleterious mutations (might be) incurring an unforeseen cost, in the long term, on the overall species fitness, through relaxation of selection Ref: Lynch M “Mutation and Human Exceptionalism: Our Future Genetic Load.” Genetics 202: 869-875 (2016)
2.
Immunodeficient murine animal models and cultured human cancer cells both serve as test subjects in the screening of anticancer effects for various chemical compounds resulting in the identification of novel ICD inducers Immunogenic cell death inducers, cytotoxic agents eliciting such manifestations as the release of HMGB1 other molecular changes include exposure of calreticulin at the cellular surface and lymphosomal ATP secretion cytotoxic activity - toxicological evaluation anticancer effects - in human neoplasms A once compromised immune system by pharmacological intervention Now sees its antineoplasic agents optimised by anticancer immunosurveillance re-activation Adaptive immune response against dead cell-associated antigens Harnessing the cell death signature, triggering ICD apoptotic stimulation Ref: Sukkurwala AQ et al. “Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set.” OncoImmunology Vol. 3, Iss.4 (2014)
3.
Enhanced levels of estrogens in the context of the cellular neurogenesis machinery Brain development compromised with paracrine signals and unwarranted apoptosis activity Abnormal development of oestrogeno-dependent reproductive physiological functions Induced by environmental traces of oestrogen-like chemical contaminations Environmental estrogens exposure - cellular reproductive foreclosure Early life exposure to micro-levels of hormone-mimicking toxic pollutants Leading to a higher incidence of reproductive failures and neurobehavioral mutants Irreversible epigenetic reprogramming induced by early life exposure to environmental estrogens Ovarian follicular developmental dysfunction putting a halt to normal reproductive functions Environmental estrogens exposure - cellular reproductive foreclosure Chemical contaminants causing the disruption of the estrogen signaling pathway Endocrine disruptors, abnormal ovarian development is underway Ref: Cruz G et al. “Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics.” J Neuroendocrinol. 26(9): 613-24 (2014)
4.
Death-receptor, binding the ligand prompting the clustering and formation of a death-inducing signalling complex Recruitment, by the Fas-associated death domain, of procaspase-8 molecules, proximal activation A cascade of caspases amplifying pro-apoptotic signals A crowd of zymogens allowing for the enzymes’mutual cleavage activation Protein-protein interactions activating upstream caspase initiators Proteolytically activated apoptotic cell death effectors Cytochrome c electron carrier, reveals itself to be crucial in cytosolic caspase-9 activation Pro-apoptotic Bcl-2 inducing the release of the aforementioned, via rupturing of the mitochondrial outer membrane Procaspase-9 and Apaf-1 forming the apoptosome (complex) Apoptotic pathway modulated via heat-shock proteins action Various downstream interactions and multiple subprogram branching Resulting in cell removal, in an orderly dismantling Precisely regulated and tightly organized death-inducing pathway; apoptosis Ref: Hengartner MO “The biochemistry of apoptosis.” Nature 407(6805):770-776 (2000)
5.
Abnormal immune response, suppression of adaptive immunity Hypersecretion of cytokines, chemokines and growth factors, all proinflammatory An observed lack of CD peripheral cells and T-lymphocytes showing low circulating cytokine production In conjunction with the absence of IFNa2 increase, disrupting the innate immune reaction cytokine storm - with a significant drop of CD peripheral cells cytokine storm - EBOLA-induced intracellular hell Defective early inflammatory responses and lymphocytic apoptosis DNA fragmentation in peripheral blood cells, reduced interferon levels and necrosis Drastically lower levels in lymphocytic populations were observed in fatally infected patients Extremely high levels of circulating inflammatory molecules, dendritic cells' functional impairment cytokine storm - with a significant loss of T-lymphocyte cells cytokine storm - EBOLA-induced intracellular hell Endothelial permeabilization, massive hemorrhagic manifestations General immune system failure during the acute phase of infection cytokine storm - with a significant drop of CD peripheral cells cytokine storm - EBOLA-induced intracellular hell cytokine storm - with a significant loss of T-lymphocyte cells cytokine storm - EBOLA-induced intracellular hell Ref: Paessler S, Walker DH “Pathogenesis of the viral hemorrhagic fevers.” Annual Review of Pathology: Mechanisms of Disease Vol. 8: 411-440 (2013)
6.
There are many a ways by which cells can be driven into proliferative, cancerous states A classical model involves changes in DNA sequences, thus causing genomes to mutate Although most mutations are of no consequences, provided they occur in non-coding regions Problems may arise when these changes affect key players of DNA-repair or cell cycle regulation Functional integrity of check point proteins may also be compromised by epigenetic modifications Normal expression of tumor suppressor genes altered, silenced by aberrant methylation patterns Repressive chromatin domain formation, from senescence to cell growth, the tables finally have turned Specific repressing sites’ methylation resulting in transcriptional de-repression CpG islands gains of methylation promoting cancerous proliferation Generally senescent cell populations undergoing transcriptional de-repression Awaiting their re-awakening through aberrant patterns of methylation Ref: Cruickshanks HA et al. “Senescent cells harbour features of the cancer epigenome.” Nature Cell Biology 15, 1495-1506 (2013)
7.
Identification of key players in determining cell viability and tumor proliferation In the context of endoplasmic reticulum stress that triggers the unfolded protein responses A challenging endeavour / faced with many obstacles / not the least of which being the elucidation Of precise molecular pathways / involved in tumorigenesis / and cellular proliferation Blocking the active domain – specific allosteric inhibition Promoting cell survival – specific allosteric inhibition Accumulation of unfolded proteins inducing homo-oligomerization Of a particular kinase/RNase enzyme, splicing the XB1 transcription factor Abnormal immune system activity / and cellular stress responses / threshold level in substrate degradation Kinase-inhibiting / RNase attenuators / disrupting oligomerization Blocking the active domain – specific allosteric inhibition Promoting cell survival – specific allosteric inhibition IREalpha unfolded protein sensor, an ineffective target to block the growth of tumors Tumor cell survival unscathed by the inhibition of the endonuclease domain of this particular transmembrane sensor Blocking the active domain - specific allosteric inhibition Promoting cell survival - specific allosteric inhibition Unfolded protein responses in stress-induced degeneration Cellular fate under control of small-molecule allosteric modulation Ref: Ghosh R et al. ”Allosteric Inhibition of the IRE1α RNase Preserves Cell Viability and Function during Endoplasmic Reticulum Stress.” Cell Vol. 158, Iss. 3 pp534-548 (2014)
8.
Necrosis, long thought to be a passive and otherwise chaotic cellular process Cellular swelling, membrane rupture, loss of intracellular contents The result of physico-chemical stress, hypoxia, IR, metabolism impairment It appears that necrosis could be a much more well-orchestrated type of cell death Precise execution mechanism, signal transduction pathways Involved in particular developmental process, tissular homeostasis Ischemia – inadequate oxygen and nutrient supply Reperfusion – increased cell death following bloodflow restoration Oxphos inhibition – intracellular ATP depletion A switch from apoptosis – to necrosis in the presence of apoptotic signalization Induction of necrosis by ligand-death receptor interaction TRAIL, Fas, TNFR1, requiring translational inhibition Blocked caspases, apoptosis prevented, necrotic death initiation Inflammatory response initiation lead by various pathogen recognition receptors Exogenous lipopolysaccharide, bacterial RNA, peptidoglycans Triggering necrotic cell death in various murine and human cellular lineages Reactive oxygen species – damages resulting in mitochondrial dysfunction RIP1 – TNF-dependent mitochondrial (re)localization Immune recognition – phosphatidylserine externalization Macrophages – necrotic cell clearance by phagocytic engulfment Ref: Vanlangenakker N et al. “Molecular mechanisms and pathophysiology of necrotic cell death.” Current Molecular Medicine 8(3):207-220. (2008)
9.
Clustered regularly interspaced short palindromic repeat associated system An endonuclease complex identified as a part of the immune system of streptococcus pyogenes A powerful tool in the context of genome editing, gene therapy and gene functional investigation Yet which still needs to be fully understood in order to minimise unintended mutation and non-specific target recognition Reprogramming of guiding gRNA sequences Targeting of a mutated gene of interest A precise DNA repair mechanism Potential clinical applications for the CRISPR/Cas9 system Cultured cells from tripronuclear human zygotes were (ab)used to further investigate the system Low efficiency in homologous (recombination) directed repair and off-target cleavage observation Endogenous homologous gene competing with the exogenous donour, causing untoward mutations Improving the specificity and accuracy of the genome editing method may necessitate years of additional experimentation Reprogramming of guiding gRNA sequences Off-target effects, mutations and mosaicism A not-so precise genome editing mechanism Potential caveats for the CRISPR/Cas9 system An otherwise low efficiency of homologous recombination directed repair, due to competing endogenous paralogs and pseudogenes Combined with off-target cleavage and interfering repair template, mosaic tripronuclear zygotes hindered by untoward mutations Ref : Puping L et al. “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.” Protein & Cell 6(5): 363–372. (2015)
10.
Infectious conditions and inflammation displaying a high serum level Of an endotoxin-induced glycoprotein, the tumor necrosis factor Found in T & B lymphocytes and natural killer cells Transduction pathway still not understood fully well Expressed on the membrane surface, cleaved by proteinases, released in a soluble form Haemorrhagic necrosis of transplanted sarcomas evidence of pro-inflammatory response Macrophages, neutrophils and endothelial cells Cellular necrosis and tissular swelling A defense against viral or parasitic infections Turned harmful for the host when in excessive production Once a glimmer of hope as a chemotherapeutic agent Contradicted by several cases of metastatic invasion In direct association with many inflammatory conditions, the tumor necrosis factor Ref: Bradley JR “TNF-mediated inflammatory disease”. J Pathol 214: 149-160 (2008)

credits

released January 24, 2018

Line-up on this record:

Taq Pol Stanley - guitars, high vox
"Gene" Simmons - bass, low vox
Deoxyribrucekulick acid - lead guitars
Eric Carrcinoma - drums

Cellhammer - drums (session)

* * *

Jay (MSc) : bass, drums, guitars, vocals

Recorded in various labs between 2016-2017.

All words and music by Jay (except where noted).

\m/ Cellular & molecular deathgrind \m/

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Tumor Necrosis Factor-alpha Neuville, Québec

Scientists, academics, gorefiends and grindheads of the world rejoice: Tumor Necrosis Factor-alpha unleashes its take on full blown Carcass-worship, topped with unique lyrical themes inspired by the most recent knowledge in state-of-the-art scientific research from the fields of cellular and molecular biology. ... more

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