Regulation of gastric acid secretion in situ by an endogenous activator protein: Studies with activator-specific antibody

Monospecific polyclonal antibody was raised against a homogenous preparation of endogenous activator protein (HAF) for the gastric H+,K+-ATPase system. Antibody was used to assess the regulatory role of the HAF in gastric acid secretion by isolated rabbit glands in situ. Immunohistochemical studies revealed aredistribution of theHAFtowards discrete intracellular zones following stimulation of the glands with histamine. The antibody, when inserted into the stimulated gastric glands by digitonin permeabilization, could effectively block the acid forming ability of the cells. The data offers, for the first time, some concrete in situ evidence for the role of the HAF as an intracellular regulator of gastric H+ transport .The manuscript was written (in the early 1990) soon after the data were collected, but never submitted to a journal with the hope of getting better gel picture and fluorescent micrograph which did not materialize due to unavoidable circumstances

Bamboo—A functionally graded composite-correlation between microstructure and mechanical strength

Bamboo is supposed to be one of the best functionally gradient composite materials available. In a piece of bamboo, not only the number of fibres (‘vascular bundles’) but also the fibre quality varies from outer to inner-most periphery. It has been observed that near the outer periphery, within 1 mm2 area, the number of fibres is approximately 8 whereas the same at the inner-most periphery is approximately 2. Again the cross-sectional shape of fibre at outer periphery is almost circular (diameter 0.14 mm) and compacted but at the inner-most periphery, a fibre (diameter of major axis 0.93 × diameter of minor axis 0.78 mm) has been sprayed, and contain matrix in it. This structural behaviour causes the variation of tensile strength, e.g., the strength of a fibre at the outer periphery is about 160 kg/mm2 and the same at the inner-most periphery is only 45 kg/mm2. It has also been observed that the matrix of bamboo can preferentially be removed from the fibre by alkali treatment. 10% NaOH can remove adhered matrix with little effect on fibres while 20% or stronger alkali reduces the strength of fibre

Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities

BACKGROUND: Glioblastoma is the deadliest and most prevalent brain tumor. Dexamethasone (DXM) is a commonly used steroid for treating glioblastoma patients for alleviation of vasogenic edema and pain prior to treatment with chemotherapeutic drugs. Temozolomide (TMZ), an alkylating agent, has recently been introduced in clinical trials for treating glioblastoma. Here, we evaluated the modulatory effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells. RESULTS: Freshly grown cells were treated with different doses of DXM or TMZ for 6 h followed by incubation in a drug-free medium for 48 h. Wright staining and ApopTag assay showed no apoptosis in cells treated with 40 μM DXM but considerable amounts of apoptosis in cells treated with 100 μM TMZ. Apoptosis in TMZ treated cells was associated with an increase in intracellular free [Ca(2+)], as determined by fura-2 assay. Western blot analyses showed alternations in the levels of Bax (pro-apoptotic) and Bcl-2 (anti-apoptotic) proteins resulting in increased Bax:Bcl-2 ratio in TMZ treated cells. Western blot analyses also detected overexpression of calpain and caspase-3, which cleaved 270 kD α-spectrin at specific sites for generation of 145 and 120 kD spectrin break down products (SBDPs), respectively. However, 1-h pretreatment of cells with 40 μM DXM dramatically decreased TMZ induced apoptosis, decreasing Bax:Bcl-2 ratio and SBDPs. CONCLUSION: Our results revealed an antagonistic effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells, implying that treatment of glioblastoma patients with DXM prior to chemotherapy with TMZ might result in an undesirable clinical outcome

Turbine blade failure in a thermal power plant

The failure of a LP (low pressure) turbine blade of a 220 MW thermal power plant is presented. The blade was made of martensitic stainless steel and the structure was tempered martensite. There was no evidence of degradation of blade material. The fracture took place at the aerofoil region, 113-mm from the root. Throughout the blade surface Si rich phases were detected. Several pits/grooves were found on the edges of the blades and chloride was detected in these pits. These were responsible for the crevice type corrosion. The probable carriers of Cl− were Ca and K, which were found on the blade. The failure mode was intergranular type. Possibly the ultimate failure was due to corrosion-fatigue

Placental microRNA methylome signatures may serve as biomarkers and therapeutic targets for prenatally opioid-exposed infants with neonatal opioid withdrawal syndrome

Introduction: The neonate exposed to opioids in utero faces a constellation of withdrawal symptoms postpartum commonly called neonatal opioid withdrawal syndrome (NOWS). The incidence of NOWS has increased in recent years due to the opioid epidemic. MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in gene regulation. Epigenetic variations in microRNAs (miRNAs) and their impact on addiction-related processes is a rapidly evolving area of research.Methods: The Illumina Infinium Methylation EPIC BeadChip was used to analyze DNA methylation levels of miRNA-encoding genes in 96 human placental tissues to identify miRNA gene methylation profiles as-sociated with NOWS: 32 from mothers whose prenatally opioid-exposed infants required pharmacologic management for NOWS, 32 from mothers whose prenatally opioid-exposed infants did not require treat-ment for NOWS, and 32 unexposed controls.Results: The study identified 46 significantly differentially methylated (FDR p-value ≤ 0.05) CpGs associated with 47 unique miRNAs, with a receiver operating characteristic (ROC) area under the curve (AUC) ≥0.75 including 28 hypomethylated and 18 hypermethylated CpGs as potentially associated with NOWS. These dysregulated microRNA methylation patterns may be a contributing factor to NOWS pathogenesis.Conclusion: This is the first study to analyze miRNA methylation profiles in NOWS infants and illustrates the unique role miRNAs might have in diagnosing and treating the disease. Furthermore, these data may provide a step toward feasible precision medicine for NOWS babies as well

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities

Glioblastoma multiforme (GBM) is a brain tumor notorious for its propensity to recur after the standard treatments of surgical resection, ionizing radiation (IR), and temozolomide (TMZ). Combined with the acquired resistance to standard treatments and recurrence, GBM is an especially deadly malignancy with hardly any worthwhile treatment options. The treatment resistance of GBM is influenced, in large part, by the contributions from two main degradative pathways in eukaryotic cells: ubiquitin-proteasome system (UPS) and autophagy. These two systems influence GBM cell survival by removing and recycling cellular components that have been damaged by treatments, as well as by modulating metabolism and selective degradation of components of cell survival or cell death pathways. There has recently been a large amount of interest in potential cancer therapies involving modulation of UPS or autophagy pathways. There is significant crosstalk between the two systems that pose therapeutic challenges, including utilization of ubiquitin signaling, the degradation of components of one system by the other, and compensatory activation of autophagy in the case of proteasome inhibition for GBM cell survival and proliferation. There are several important regulatory nodes which have functions affecting both systems. There are various molecular components at the intersections of UPS and autophagy pathways that pose challenges but also show some new therapeutic opportunities for GBM. This review article aims to provide an overview of the recent advancements in research regarding the intersections of UPS and autophagy with relevance to finding novel GBM treatment opportunities, especially for combating GBM treatment resistance

Histone deacetylase enzymes and selective histone deacetylase inhibitors for antitumor effects and enhancement of antitumor immunity in glioblastoma

Glioblastoma multiforme (GBM), which is the most common primary central nervous system malignancy in adults, has long presented a formidable challenge to researchers and clinicians alike. Dismal 5-year survival rates of the patients with these tumors and the ability of the recurrent tumors to evade primary treatment strategies have prompted a need for alternative therapies in the treatment of GBM. Histone deacetylase (HDAC) inhibitors are currently a potential epigenetic therapy modality under investigation for use in GBM with mixed results. While these agents show promise through a variety of proposed mechanisms in the pre-clinical realm, only several of these agents have shown this same promise when translated into the clinical arena, either as monotherapy or for use in combination regimens. This review will examine the current state of use of HDAC inhibitors in GBM, the mechanistic rationale for use of HDAC inhibitors in GBM, and then examine an exciting new mechanistic revelation of certain HDAC inhibitors that promote antitumor immunity in GBM. The details of this antitumor immunity will be discussed with an emphasis on application of this antitumor immunity towards developing alternative therapies for treatment of GBM. The final section of this article will provide an overview of the current state of immunotherapy targeted specifically to GBM

Bone morphogenic protein signaling in spinal cord injury

Spinal cord injury (SCI) is a debilitating injury that results from traumatic or non-traumatic insults to the spinal cord, causing significant impairment of the patient’s activity and quality of life. Bone morphogenic proteins (BMPs) are a group of polyfunctional cytokines belonging to the transforming growth factor beta superfamily that regulates a wide variety of cellular functions in healthy and disease states. Recent studies suggest that dysregulation of BMP signaling is involved in neuronal demyelination and death after traumatic SCI. The focus of this article is to describe our current understanding of the role of BMP signaling in the regulation of cell fate, proliferation, apoptosis, autophagy, and inflammation in traumatic SCI. First, we will describe the expression of BMPs and pattern of BMP signaling before, and after traumatic SCI in rodent models and in vitro. Next, we will discuss the role of BMP in the regulation of neuronal and glial cell differentiation, survival, functional recovery from traumatic SCI, and the gap in knowledge in this area that requires further investigation to improve SCI prognosis