ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.

Although the role of the ErbB2/HER2 oncogene in cancers has been extensively studied, how ErbB2 is regulated remains poorly understood. A novel microRNA, mir-4728, was recently found within an intron of the ErbB2 gene. However, the function and clinical relevance of this intronic miRNA are completely unknown. Here, we demonstrate that mir-4728 is a negative regulator of MAPK signaling through directly targeting the ERK upstream kinase MST4 and exerts numerous tumor-suppressive properties in vitro and in animal models. Importantly, our patient sample study shows that mir-4728 was under-expressed in breast tumors compared with normal tissue, and loss of mir-4728 correlated with worse overall patient survival. These results strongly suggest that mir-4728 is a tumor-suppressive miRNA that controls MAPK signaling through targeting MST4, revealing mir-4728's significance as a potential prognostic factor and target for therapeutic intervention in cancer. Moreover, this study represents a conceptual advance by providing strong evidence that a tumor-suppressive miRNA can antagonize the canonical signaling of its host oncogene.

The metabolic effect of thyrotropin releasing hormone (trh) and norepinephrine (ne) in warm-acclimated obese rats - biomed 2011.

We have studied the effects of chronic peripheral infusion of thyrotropin releasing hormone (TRH) and norepinephrine (NE) alone and together. Do these hormones additively affect energy balance and body weight similarly in obese animals? 20 obese (fa/fa) Zucker strain rats were studied. Food intake, body weight and resting metabolic rate (RMR) were measured over a 14 day period. We confirmed that in these animals NE stimulated RMR, but with parallel stimulation of appetite so that weight gain continued; TRH stimulated RMR but inhibited food intake so that rate of weight gain was reduced. TRH and NE together acted to further enhance RMR, but the inhibitory and stimulatory effects on food intake cancelled out. Thus a negative energy balance resulted in this group of animals; however, resultant weight loss was moderate in obese compared to previously studied lean animals. We suggest like we previously reported that the relative insensitivity of the obese to TRH and NE together reflects the inability of their brown adipose tissue to respond to thermogenic agents, even when chronically administered.

The effect of neuropeptide y and norepinepherine on food intake and body weight - biomed 2010.

NPY has been reported to co-exist within catecholaminergic neurons of the central and peripheral nervous systems. The functional significance in noradrenergic neurons has been related to the vasomotor effects of NPY which complement and interact with NE which is known to have central and peripheral effects on resting metabolic rate (RMR), food intake and body weight of rats. We have studied the effect of chronic peripheral administration of NPY on the metabolic action of NE in lean and obese adult male rats. A group of 20 adult male obese (Jaffa) Zucker rats were acclimated to environmental temperature of either 28 degrees C or 17 degrees C. Each group was divided into 5 subgroups: (I) untreated controls; (II) Carrier-treated Controls; (III) NPY treated; (IV) NE treated and (V) NPY+NE treated. In subgroups II-V , AlzetTm (2002) osmotic minipumps were implanted under the skin in the interscapular region. Pumps were filled with carrier alone (subgroups II) plus NPY (subgroups III), or NE (subgroups IV), or both (subgroups V). Delivery rates were calculated to be 03 microg/h NPY ; 20 microg/h NE, extending over a period of 14 days. Starting from day 2, cumulative food intake and cumulative changes in total body weight were measured every two days.. In warm environmental the combined treatment with NE and NPY was the only treatment that caused significant reduction of total body weight by inhibiting food intake. In the cold environment the NE and NPY together showed similar but less enhancing effect on body weight, this was mainly due to the significant depression of food.

The synergistic effect of sustained administration of neuropeptide y and norepinephrine on the brown fat metabolic activity in cold acclimated obese rats - biomed 2009.

In previous study, we have reported the effects of chronic peripheral infusion of Neuropeptide Y (NPY) and norepinephrine (NE) alone and together on the metabolic activity of the brown adipose tissue (BAT) in warm acclimated studies in genetically obese reflected in the changes in the size of the triglyceride droplets (TGD) of this tissue. Do these hormones have the same effects on cold-acclimated genetically obese animals? Twenty obese (fa/fa) Zucker strain rats were studied. Again, we can confirm that in these animals NE enhanced the metabolic activity of BAT; NPY had an enhancing effect but with lower level than NE. The combined treatment of rats with both hormones resulted in the highest level of metabolic activity of these animals. We suggest that these animals have higher response to these treatments when they are acclimated to cold environment.

The effect of npy and norepinephrine on the triglyceride droplets in brown adipose tissue in obese warm acclimated rats.

We have studied the effects of chronic peripheral infusion of Neuropeptide Y (NPY) and norepinephrine (NE) alone and together. Do these hormones additively affect the metabolic activity of Brown adipost tissue (BAT in obese animals? 20 obese (fa/fa) Zucker strain rats were studied. The diameter of the triglyceride droplets (TGDs) was measured as an indicator of the BAT metabolic activity. We confirmed that in these animals NE alone did not stimulated BAT metabolic activity. Neither did NPY alone. NPY and NE together caused significant induction of BAT metabolic activity as indicated by severe reduction in the TGD diameter.

The effect of TRH and norepinephrine on the triglyceride droplets (TGD) in brown adipose tissue in warm acclimated rats.

We have studied the effects of chronic peripheral infusion of thyrotropin releasing hormone (TRH) and norepinephrine (NE) alone and together. Do these hormones additively affect energy balance and body weight similarly in obese animals? 20 obese (fa/fa) Zucker strain rats were studied. Food intake, body weight and resting metabolic rate (RMR) were measured over a 14 day period. We confirmed that in these animals NE stimulated RMR, but with parallel stimulation of appetite so that weight gain continued; TRH stimulated RMR but inhibited food intake so that rate of weight gain was reduced. TRH and NE together acted to further enhance RMR, but the inhibitory and stimulatory effects on food intake cancelled out. Thus a negative energy balance resulted in this group of animals; however, resultant weight loss was moderate in obese compared to previously studied lean animals. We suggest that the relative insensitivity of the obese to TRH and NE together reflects the inability of their brown adipose tissue to respond to thermogenic agents, even when chronically administered.

The metabolic effect of thyrotropin releasing hormone (TRH) and norepinephrine (NE) in cold-acclimated obese rats.

We have studied the effects of chronic peripheral infusion of thyrotropin releasing hormone (TRH) and norepinephrine (NE) alone and together. Do these hormones additively affect energy balance and body weight similarly in obese animals? 20 obese (fa/fa) Zucker strain rats were studied. Food intake, body weight and resting metabolic rate (RMR) were measured over a 14 day period. We confirmed that in these animals NE stimulated RMR, but with parallel stimulation of appetite so that weight gain continued; TRH stimulated RMR but inhibited food intake so that rate of weight gain was reduced. TRH and NE together acted to further enhance RMR, but the inhibitory and stimulatory effects on food intake cancelled out. Thus a negative energy balance resulted in this group of animals; however, resultant weight loss was moderate in obese compared to previously studied lean animals. We suggest that the relative insensitivity of the obese to TRH and NE together reflects the inability of their brown adipose tissue to respond to thermogenic agents, even when chronically administered.

Thyrotropin releasing hormone (TRH) potentiates the metabolic effect of norepinephrine (NE) in warm-acclimated lean and obese rats.

We have studied the effects of chronic peripheral infusion of thyrotropin releasing hormone (TRH) and norepinephrine (NE) alone and together. Do these hormones additively affect energy balance and body weight similarly in lean and obese animals? 20 each lean Wistar and obese (fa/fa) Zucker strain rats were studied. Food intake, body weight and resting metabolic rate (RMR) were measured over a 14 day period. We confirmed that in the obese animals, separately the hormones act as in the lean: NE stimulated RMR, but with parallel stimulation of appetite so that weight gain continued; TRH stimulated RMR but inhibited food intake so that rate of weight gain was reduced. TRH and NE together acted to further enhance RMR, but the inhibitory and stimulatory effects on food intake cancelled out. Thus a negative energy balance resulted in both groups; however, resultant weight loss was profound in lean but only moderate in obese. We suggest that the relative insensitivity of the obese to TRH and NE together reflects the inability of their brown adipose tissue to respond to thermogenic agents, even when chronically administered.

Population genetic structure of the western mosquitofish, Gambusia affinis, in a highly channelized portion of the San Antonio River in San Antonio, TX.

Population genetic assessments were performed on populations of the mosquitofish, Gambusia affinis, sampled at seven sites along a 10 km reach of the upper San Antonio River in San Antonio, TX. Mosquitofish populations were sampled from the downtown area, known as the "Riverwalk", where the river is concrete lined, deeply pooled, and receives heavy tour boat traffic. Populations were also sampled from sites upstream and downstream from the Riverwalk. Allozyme electrophoresis was performed on approximately 50 individuals from each site. Five of 12 loci surveyed were polymorphic (95% criterion). Exact tests over all loci for all populations indicated that allele frequencies differed significantly among sites. Allele frequencies of the upstream population were significantly different from the Riverwalk populations. Differences resulted primarily from significant decreases in frequencies of rare alleles at MDH-2* and two GPI* loci in the downtown area. Mean dissolved oxygen measurements were also significantly lower at Riverwalk sites. These results suggest that selective forces such as non-point source runoff or low dissolved oxygen, perhaps in combination with limited migration due to numerous dams, have reduced genetic diversity of populations in the downtown area.

Effects of acute leptin administration on the differences in proton leak rate in liver mitochondria from ob/ob mice compared to lean controls.

In this investigation, the effects on proton leak of leptin administration to ob/ob mice was measured for liver mitochondria. We and others have shown that proton leak is approximately 3 times greater in liver mitochondria from ob/ob mice compared to lean controls at any given membrane potential. The results are consistent with obese mammals having higher lean mass-specific metabolic rates compared to lean controls. The increase in proton leak rate at any given membrane potential cannot be explained by the presence of free fatty acids associated with mitochondria isolated from the obese animals. The difference in proton leak must therefore represent a real difference in inner membrane permeability. Acute leptin (OB protein) administration restores the liver mitochondrial proton leak rate of ob/ob mice to that of lean controls. There was no effect on proton leak rate of liver mitochondria from sham-treated ob/ob mice. These novel results indicate a role for leptin, either directly or indirectly, in regulating the efficiency of oxidative phosphorylation.

Indirect measurement of mitochondrial proton leak and its application.

In mitochondria, ATP synthesis is coupled to oxygen consumption by the proton electrochemical gradient established across the mitochondrial inner membrane in a process termed oxidative phosphorylation. It has long been known from stoichiometric studies that ATP synthesis is not perfectly coupled to oxygen consumption. The major inefficiency in the system is leakage of protons across the mitochondrial inner membrane driven by the proton electrochemical gradient. The kinetics of the proton leak can be determined indirectly, by measuring the oxygen consumption of mitochondria under non-phosphorylating conditions (plus oligomycin) as a function of the proton electrochemical gradient. This experimental system provides a convenient means to investigate inner membrane permeability to protons and the effect of factors that may effect that permeability. In this paper we review some results from our laboratory of indirect measurement of mitochondrial proton leak and how it has been applied to investigate the effect of aging, obesity and thyroid status on proton leak. The results show that (i) proton leak in isolated liver mitochondria is not significantly different in a comparison of young and old rats, in contrast (ii) there is an apparent increase in proton leak in in situ mitochondria in hepatocytes from old rats when compared to those from young rats, (iii) proton leak in neuronal mitochondria in situ in synaptosomes is not significantly different in young and old rats, (iv) proton leak is greater in isolated liver mitochondria from ob/ob mice compared to lean controls, (v) acute leptin (OB protein) administration restores the increased leak rate in isolated liver mitochondria from ob/ob mice to that of lean controls, (vi) administration of thyroid hormone (T3) increases proton leak in rat muscle mitochondria, and (vii) proton leak in muscle mitochondria is insensitive to the presence of GDP. It is proposed that the experimental system described here for measuring proton leak, is an ideal functional assay for determining whether the novel uncoupling proteins increase inner membrane permeability to protons.

Hopwood, affirmative action, and deaf education.

Minority-deaf students constitute 43.5% of the deaf school-age population, yet only 11.7% of teachers and administrators in programs serving deaf students are persons of color. The ruling in Hopwood v. State of Texas (1996) banned the use of race as a major determinant in admissions to colleges and universities in Louisiana, Mississippi, and Texas. This ruling, along with the current backlash against affirmative action policies, has hindered college administrators' efforts to recruit minorities in deaf education. We discuss Hopwood, affirmative action policies, and how both affect deaf education teacher training today. We also present an eight-step action plan for teacher-training colleges and universities to meet the need to increase the number of minority teachers and leaders and encourage state educational agencies and schools for the Deaf to do likewise.

Changes in cytochrome oxidase activity in brown adipose tissue during oestrous cycle in the rat.

Cold-acclimated female Wistar rats were killed at a known phase of the oestrous cycle to investigate whether natural fluctuations of female sex steroids during the cycle are mirrored by changes in brown adipose tissue (BAT) activity. Four phases: proestrus, oestrus, dioestrus I and dioestrus II, were identified by the cells types appearing in vaginal smears. BAT was removed and analysed for composition and specific indicators of BAT activity. No changes in BAT mass, protein or mitochondrial content were detected during the cycle. Thermogenesis was also unchanged as judged by both lipid multilocularity and mitochondrial GDP-binding. However, cytochrome c oxidase (COX) activity did cycle with a minimum at proestrus and a maximum at dioestrus I. The involvement of oestradiol in such a cycle is suggested by the fact that oestradiol treatment decreased COX activity to values similar to those found in proestrus. The physiological function of a cyclic oxidative capacity remains to be elucidated.

What's up, Billy Jo? Deaf children and bilingual-bicultural instruction in east-central Texas.

Seven deaf children attended a bilingual-bicultural (bi-bi) prekindergarten, kindergarten, and first grade from 1993 to 1996 in an east-central Texas public school. The children had diverse backgrounds (African American, Hispanic, White) and various intellectual, cognitive, and linguistic abilities. We detail the backgrounds of the seven children and their families and describe three bi-bi classrooms. We present standardized test scores on cognition (Bracken Test of Basic Concepts) and academic achievement (Stanford Achievement Test, 9th edition, and Woodcock-Johnson Psycho-Educational Battery). When, with one exception, the children completed first grade, they all tested at grade level. (The exception was a younger child who had only completed kindergarten but who nonetheless tested at the first-grade level). We interpret our findings in light of theories of first- and second-language acquisition and discuss the feasibility of establishing bi-bi programs in areas where no large Deaf community exists. We also note our plans to evaluate the seven children again, at the end of second grade in spring 1997.

Synergistic action by neuropeptide Y (NPY) and norepinephrine (NE) on food intake, metabolic rate, and brown adipose tissue (BAT) causes remarkable weight loss in the obese (fa/fa) Zucker rat.

NPY has been reported to co-exist within catecholaminergic neurons of the central and peripheral nervous systems. The functional significance in noradrenergic neurons has been related to the vasomotor effects of NPY which complement and interact with NE which is known to have central and peripheral effects on resting metabolic rate (RMR), food intake and body weight of rats. We have studied the effect of chronic peripheral administration of NPY on the metabolic action of NE in obese adult male rats. A group of 20 adult male obese (fa/fa) Zucker rats were acclimated to environmental temperature of either 28 degrees C or 17 degrees C. Each group was divided into 5 subgroups: (I) untreated controls; (II) Carrier-treated Controls; (III) NPY treated; (IV) NE treated and (V) NPY + NE treated. In subgroups II-V, Alzet (2002) osmotic minipumps were implanted under the skin in the interscapular region. Pumps were filled with carrier alone (subgroups II) plus NPY (subgroups III), or NE (subgroups IV), or both (subgroups V). Delivery rates were calculated to be 0.5 microgram/h NPY; 20 micrograms/h NE, extending over a period of 14 days. Starting from day 2, cumulative food intake and cumulative changes in total body weight were measured every two days. RMR of the animals was measured on days 2, 8, and 14 (indirectly as minimal oxygen consumption). On day 15 animals were sacrificed and specimens of the interscapular BAT were fixed for microscopic examination and measurement of the cross-sectional area of the triglyceride droplets as index for tissue activity. In warm environmental conditions the combined treatment with NE and NPY was the only treatment that caused significant reduction of total body weight by inhibiting food intake and enhancing RMR. The involvement of BAT in this function was observed. In the cold environment the NE and NPY together showed similar but less enhancing effect on body weight; this was mainly due to the significant depression of food intake and slight metabolic response. BAT of this group showed significant response to the combined treatment and slight response to the separate treatments with either NE or NPY.

Voluntary contraction shortens peripheral conduction time in response to transcranial magnetic stimulation of the brain.

We investigated the effects of voluntary contraction on peripheral conduction time in response to transcranial magnetic stimulation (TMS) of the brain in 10 normal subjects. We obtained surface recordings of compound muscle action potentials (CMAP) from the abductor digiti minimi muscle (ADM) and nerve action potentials (NAP) from the ulnar nerve, at rest and during contraction (10% of maximal voluntary contraction) in response to TMS delivered at 100% output using a coil shaped like a figure 8. The distance between the two recording electrodes was 10 cm. The distal latency in response to TMS was calculated by subtracting the NAP latency from the CMAP latency. Distal latency was also measured by recording ADM responses to supramaximal electrical stimulation (ES) 10 cm proximal to the recording electrode. TMS-induced distal latency was significantly shorter during voluntary contraction than at rest (P < 0.0001). There was no significant difference between TMS-induced distal latency during contraction and ES-induced distal latency. TMS-induced distal latencies at rest and during contraction were correlated with the ES-induced distal latencies (r2 = 0.468, P = 0.028 and r2 = 0.769, P = 0.0009, respectively). Our results showed that the peripheral conduction time in response to TMS was related to the activity of the target muscle and to the fastest conduction velocity of the target nerve. Voluntary contraction reduced the peripheral conduction time in response to TMS.