A longstanding question in taste research concerns taste coding and, in particular, how broadly are individual taste bud cells tuned to taste qualities (sweet, bitter, umami, salty, and sour). Taste bud cells express G-protein-coupled receptors for sweet, bitter, or umami tastes but not in combination. However, responses to multiple taste qualities have been recorded in individual taste cells. We and others have shown previously there are two classes of taste bud cells directly involved in gustatory signaling: “receptor” (type II) cells that detect and transduce sweet, bitter, and umami compounds, and “presynaptic” (type III) cells. We hypothesize that receptor cells transmit their signals to presynaptic cells. This communication between taste cells could represent a potential convergence of taste information in the taste bud, resulting in taste cells that would respond broadly to multiple taste stimuli. We tested this hypothesis using calcium imaging in a lingual slice preparation. Here, we show that receptor cells are indeed narrowly tuned: 82% responded to only one taste stimulus. In contrast, presynaptic cells are broadly tuned: 83% responded to two or more different taste qualities. Receptor cells responded to bitter, sweet, or umami stimuli but rarely to sour or salty stimuli. Presynaptic cells responded to all taste qualities, including sour and salty. These data further elaborate functional differences between receptor cells and presynaptic cells, provide strong evidence for communication within the taste bud, and resolve the paradox of broad taste cell tuning despite mutually exclusive receptor expression.

Phospholipase C–type β2 (PLCβ2) is expressed in a subset of cells within mammalian taste buds. This enzyme is involved in the transduction of sweet, bitter, and umami stimuli and thus is believed to be a marker for gustatory sensory receptor cells. We have developed transgenic mice expressing green fluorescent protein (GFP) under the control of the PLCβ2 promoter to enable one to identify these cells and record their physiological activity in living preparations. Expression of GFP (especially in lines with more than one copy integrated) is strong enough to be detected in intact tissue preparations using epifluorescence microscopy. By immunohistochemistry, we confirmed that the overwhelming majority of cells expressing GFP are those that endogenously express PLCβ2. Expression of the GFP transgene in circumvallate papillae occurs at about the same time during development as endogenous PLCβ2 expression. When loaded with a calcium-sensitive dye in situ, GFP-positive taste cells produce typical Ca²⁺ responses to a taste stimulus, the bitter compound cycloheximide. These PLCβ2 promoter–GFP transgenic lines promise to be useful for studying taste transduction, sensory signal processing, and taste bud development.

Cyclic AMP (cAMP) and Ca²⁺ are two ubiquitous second messengers in transduction pathways downstream of receptors for hormones, neurotransmitters and local signals. The availability of fluorescent Ca²⁺ reporter dyes that are easily introduced into cells and tissues has facilitated analysis of the dynamics and spatial patterns for Ca²⁺ signaling pathways. A similar dissection of the role of cAMP has lagged because indicator dyes do not exist. Genetically encoded reporters for cAMP are available but they must be introduced by transient transfection in cell culture, which limits their utility. We report here that we have produced a strain of transgenic mice in which an enhanced cAMP reporter is integrated in the genome and can be expressed in any targeted tissue and with tetracycline induction. We have expressed the cAMP reporter in β-cells of pancreatic islets and conducted an analysis of intracellular cAMP levels in relation to glucose stimulation, Ca²⁺ levels, and membrane depolarization. Pancreatic function in transgenic mice was normal. In induced transgenic islets, glucose evoked an increase in cAMP in β-cells in a dose-dependent manner. The cAMP response is independent of (in fact, precedes) the Ca²⁺ influx that results from glucose stimulation of islets. Glucose-evoked cAMP responses are synchronous in cells throughout the islet and occur in 2 phases suggestive of the time course of insulin secretion. Insofar as cAMP in islets is known to potentiate insulin secretion, the novel transgenic mouse model will for the first time permit detailed analyses of cAMP signals in β-cells within islets, i.e. in their native physiological context. Reporter expression in other tissues (such as the heart) where cAMP plays a critical regulatory role, will permit novel biomedical approaches.

To compare features of hepatocellular carcinoma (HCC) in Hispanics to those of African Americans and Whites. Patients treated for HCC at an urban tertiary medical center from 2005 to 2011 were identified from a tumor registry. Data were collected retrospectively, including demographics, comorbidities, liver disease characteristics, tumor parameters, treatment, and survival (OS) outcomes. OS analyses were performed using Kaplan-Meier method. One hundred and ninety-five patients with HCC were identified: 80.5% were male, and 22% were age 65 or older. Mean age at HCC diagnosis was 59.7 ± 9.8 years. Sixty-one point five percent of patients had Medicare or Medicaid; 4.1% were uninsured. Compared to African American (31.2%) and White (46.2%) patients, Hispanic patients (22.6%) were more likely to have diabetes (P = 0.0019), hyperlipidemia (P = 0.0001), nonalcoholic steatohepatitis (NASH) (P = 0.0021), end stage renal disease (P = 0.0057), and less likely to have hepatitis C virus (P < 0.0001) or a smoking history (P < 0.0001). Compared to African Americans, Hispanics were more likely to meet criteria for metabolic syndrome (P = 0.0491), had higher median MELD scores (P = 0.0159), ascites (P = 0.008), and encephalopathy (P = 0.0087). Hispanic patients with HCC had shorter OS than the other racial groups (P = 0.020), despite similarities in HCC parameters and treatment. In conclusion, Hispanic patients with HCC have higher incidence of modifiable metabolic risk factors including NASH, and shorter OS than African American and White patients.

• Significant progress has been made on the treatment of MM during past two decades. • Acquired drug-resistance continues to drive early relapse in primary refractory MM. • XPO1 over-expression and cargo mislocalization are associated with drug-resistance. • XPO1 inhibitor selinexor restores drug sensitivity to subsets of RR-MM cells.