A novel subtype of sporadic Creutzfeldt-Jakob disease with PRNP codon 129MM genotype and PrP plaques.

The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt-Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrP type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrP T1 mimic those of sCJDMM1, the most common human prion disease.

Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney.

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO) and water into bicarbonate (HCO) and protons (H), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid-base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO in specific nephron segments. Among these transporters are the Na-coupled HCO transporters (NCBTs) and the Cl-HCO exchangers (AEs)-members of the "solute-linked carrier" 4 (SLC4) family.

Distinguishing among HCO 3- , CO 3= , and H + as Substrates of Proteins That Appear To Be "Bicarbonate" Transporters.

Background: Differentiating among HCO 3- , CO 3= , and H + movements across membranes has long seemed impossible. We now seek to discriminate unambiguously among three alternate mechanisms: the inward flux of 2 HCO 3- (mechanism 1), the inward flux of 1 CO 3= (mechanism 2), and the CO 2 /HCO 3- -stimulated outward flux of 2 H + (mechanism 3).

Methods: As a test case, we use electrophysiology and heterologous expression in Xenopus oocytes to examine SLC4 family members that appear to transport "bicarbonate" ("HCO 3- ").

Carbon dioxide transport across membranes.

Carbon dioxide (CO) movement across cellular membranes is passive and governed by Fick's law of diffusion. Until recently, we believed that gases cross biological membranes exclusively by dissolving in and then diffusing through membrane lipid. However, the observation that some membranes are CO impermeable led to the discovery of a gas molecule moving through a channel; namely, CO diffusion through aquaporin-1 (AQP1).

The therapeutic importance of acid-base balance.

Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate).

Case Report: Histopathology and Prion Protein Molecular Properties in Inherited Prion Disease With a Seven-Octapeptide Repeat Insertion.

The insertion of additional 168 base pair containing seven octapeptide repeats in the prion protein (PrP) gene region spanning residues 51-91 is associated with inherited prion disease. In 2008, we reported the clinical features of a novel seven-octapeptide repeat insertion (7-OPRI) mutation coupled with codon 129 methionine (M) homozygosity in the PrP gene of a 19-year-old man presenting with psychosis and atypical dementia, and 16-year survival. Here, we describe the histopathological and PrP molecular properties in the autopsied brain of this patient.

Co-existence of PrP types 1 and 2 in sporadic Creutzfeldt-Jakob disease of the VV subgroup: phenotypic and prion protein characteristics.

We report a detailed study of a cohort of sporadic Creutzfeldt-Jakob disease (sCJD) VV1-2 type-mixed cases (valine homozygosity at codon 129 of the prion protein, PrP, gene harboring disease-related PrP, PrP, types 1 and 2). Overall, sCJDVV1-2 subjects showed mixed clinical and histopathological features, which often correlated with the relative amounts of the corresponding PrP type. However, type-specific phenotypic characteristics were only detected when the amount of the corresponding PrP type exceeded 20-25%.

Role of Carbonic Anhydrases and Inhibitors in Acid-Base Physiology: Insights from Mathematical Modeling.

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO) and water (HO) into bicarbonate (HCO) and protons (H). These enzymes impact numerous physiological processes that occur within and across the many compartments in the body. Within compartments, CAs promote rapid H buffering and thus the stability of pH-sensitive processes.

Na/HCO Cotransporter NBCn2 Mediates HCO Reclamation in the Apical Membrane of Renal Proximal Tubules.

The kidney maintains systemic acid-base balance by reclaiming from the renal tubule lumen virtually all HCO filtered in glomeruli and by secreting additional H to titrate luminal buffers. For proximal tubules, which are responsible for about 80% of this activity, it is believed that HCO reclamation depends solely on H secretion, mediated by the apical Na/H exchanger NHE and the vacuolar proton pump. However, and the proton pump cannot account for all HCO reclamation.

Nitric oxide reduces paracellular resistance in rat thick ascending limbs by increasing Na and Cl permeabilities.

About 50% of the Na reabsorbed in thick ascending limbs traverses the paracellular pathway. Nitric oxide (NO) reduces the permselectivity of this pathway via cGMP, but its effects on absolute Na ([Formula: see text]) and Cl ([Formula: see text]) permeabilities are unknown. To address this, we measured the effect of l-arginine (0.

Distinct Cellular Locations of Carbonic Anhydrases Mediate Carbon Dioxide Control of Stomatal Movements.

Elevated carbon dioxide (CO2) in leaves closes stomatal apertures. Research has shown key functions of the β-carbonic anhydrases (βCA1 and βCA4) in rapid CO2-induced stomatal movements by catalytic transmission of the CO2 signal in guard cells. However, the underlying mechanisms remain unclear, because initial studies indicate that these Arabidopsis (Arabidopsis thaliana) βCAs are targeted to distinct intracellular compartments upon expression in tobacco (Nicotiana benthamiana) cells.

Mathematical modeling of acid-base physiology.

pH is one of the most important parameters in life, influencing virtually every biological process at the cellular, tissue, and whole-body level. Thus, for cells, it is critical to regulate intracellular pH (pHi) and, for multicellular organisms, to regulate extracellular pH (pHo). pHi regulation depends on the opposing actions of plasma-membrane transporters that tend to increase pHi, and others that tend to decrease pHi.

Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase IV enhances CO2 fluxes across Xenopus oocyte plasma membranes.

Human carbonic anhydrase IV (CA IV) is GPI-anchored to the outer membrane surface, catalyzing CO2/HCO3 (-) hydration-dehydration. We examined effects of heterologously expressed CA IV on intracellular-pH (pHi) and surface-pH (pHS) transients caused by exposing oocytes to CO2/HCO3 (-)/pH 7.50.

Evidence from mathematical modeling that carbonic anhydrase II and IV enhance CO2 fluxes across Xenopus oocyte plasma membranes.

Exposing an oocyte to CO2/HCO3 (-) causes intracellular pH (pHi) to decline and extracellular-surface pH (pHS) to rise to a peak and decay. The two companion papers showed that oocytes injected with cytosolic carbonic anhydrase II (CA II) or expressing surface CA IV exhibit increased maximal rate of pHi change (dpHi/dt)max, increased maximal pHS changes (ΔpHS), and decreased time constants for pHi decline and pHS decay. Here we investigate these results using refinements of an earlier mathematical model of CO2 influx into a spherical cell.

Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase II enhances CO2 fluxes across Xenopus oocyte plasma membranes.

The α-carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the interconversion of CO2 and HCO3 (-). Here, we focus on human CA II (CA II), a ubiquitous cytoplasmic enzyme. In the second paper in this series, we examine CA IV at the extracellular surface.

A reaction-diffusion model of CO2 influx into an oocyte.

We have developed and implemented a novel mathematical model for simulating transients in surface pH (pH(S)) and intracellular pH (pH(i)) caused by the influx of carbon dioxide (CO(2)) into a Xenopus oocyte. These transients are important tools for studying gas channels. We assume that the oocyte is a sphere surrounded by a thin layer of unstirred fluid, the extracellular unconvected fluid (EUF), which is in turn surrounded by the well-stirred bulk extracellular fluid (BECF) that represents an infinite reservoir for all solutes.

Interpretation of NMR spectroscopy human brain data with a multi-compartment computational model of cerebral metabolism.

One of the main difficulties in studying human brain metabolism at rest and during neuronal stimulation is that direct quantitative information of metabolite and intermediate concentrations in real time from in vivo and in situ brain cells is extremely difficult to obtain. We present a new six compartment dynamic computational model of the astrocyte-glutamatergic neuron cellular complex, previously used and validated for steady state investigations [1],which utilizes Michaelis-Menten type kinetic expressions for the reaction fluxes and transport rates. The model is employed to interpret experimental data (total tissue concentrations of glucose, lactate, aspartate, and glutamate) collected via NMR spectroscopy [2] in terms of compartmentalized metabolism.

Energetics of inhibition: insights with a computational model of the human GABAergic neuron-astrocyte cellular complex.

We investigate metabolic interactions between astrocytes and GABAergic neurons at steady states corresponding to different activity levels using a six-compartment model and a new methodology based on Bayesian statistics. Many questions about the energetics of inhibition are still waiting for definite answers, including the role of glutamine and lactate effluxed by astrocytes as precursors for γ-aminobutyric acid (GABA), and whether metabolic coupling applies to the inhibitory neurotransmitter GABA. Our identification and quantification of metabolic pathways describing the interaction between GABAergic neurons and astrocytes in connection with the release of GABA makes a contribution to this important problem.

Astrocytes as the glucose shunt for glutamatergic neurons at high activity: an in silico study.

The question of the preferred substrate of glutamatergic neurons at high neural activity has been vibrantly debated for over a decade since the classical hypothesis (CH) of the primacy of glucose has been challenged by the astrocyte-neuron lactate shuttle hypothesis (ANLSH), which replaces the primacy of glucose with astrocyte produced lactate. We perform Bayesian Flux Balance Analysis (BFBA) with a new mathematical model of cellular brain energetics, comprising detailed biochemical pathways in and between astrocytes and glutamatergic neurons and partitioning of each cell type into cytosol and mitochondria. Supported by the results of our in silico studies, which are in remarkable agreement with previously published results, we posit the Glucose Shunt Hypothesis (GSH) that during high activity, the inhibition of the phosphofructokinase (PFK) enzyme in neuron impairs neuronal glycolysis, enabling the process by which lactate effluxed by astrocytes is taken up by glutamatergic neurons, whereas at low activity, glucose remains the preferred substrate for neurons.