Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.

Disrupting particular mitochondrial fission and fusion proteins leads to the death of specific neuronal populations; however, the normal functions of mitochondrial fission in neurons are poorly understood, especially in vivo, which limits the understanding of mitochondrial changes in disease. Altered activity of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) may contribute to the pathophysiology of several neurologic diseases. To study Drp1 in a neuronal population affected by Alzheimer's disease (AD), stroke, and seizure disorders, we postnatally deleted Drp1 from CA1 and other forebrain neurons in mice (CamKII-Cre, Drp1lox/lox (Drp1cKO)). Although most CA1 neurons survived for more than 1 year, their synaptic transmission was impaired, and Drp1cKO mice had impaired memory. In Drp1cKO cell bodies, we observed marked mitochondrial swelling but no change in the number of mitochondria in individual synaptic terminals. Using ATP FRET sensors, we found that cultured neurons lacking Drp1 (Drp1KO) could not maintain normal levels of mitochondrial-derived ATP when energy consumption was increased by neural activity. These deficits occurred specifically at the nerve terminal, but not the cell body, and were sufficient to impair synaptic vesicle cycling. Although Drp1KO increased the distance between axonal mitochondria, mitochondrial-derived ATP still decreased similarly in Drp1KO boutons with and without mitochondria. This indicates that mitochondrial-derived ATP is rapidly dispersed in Drp1KO axons, and that the deficits in axonal bioenergetics and function are not caused by regional energy gradients. Instead, loss of Drp1 compromises the intrinsic bioenergetic function of axonal mitochondria, thus revealing a mechanism by which disrupting mitochondrial dynamics can cause dysfunction of axons

Fluctuation-Facilitated Charge Migration along DNA

We propose a model Hamiltonian for charge transfer along the DNA double helix with temperature driven fluctuations in the base pair positions acting as the rate limiting factor for charge transfer between neighboring base pairs. We compare the predictions of the model with the recent work of J.K. Barton and A.H. Zewail (Proc.Natl.Acad.Sci.USA, {\bf 96}, 6014 (1999)) on the unusual two-stage charge transfer of DNA.Comment: 4 pages, 2 figure

A Simple Linear Time Algorithm for Computing a 1-Median on Cactus Graphs

We address the problem of finding a 1-median on a cactus graph. The problem has already been solved in linear time by the algorithms of Burkard and Krarup (1998), and Lan and Wang (2000). These algorithms are complicated and need efforts. Hence, we develop in this paper a simpler algorithm. First, we construct a condition for a cycle that contains a 1-median or for a vertex that is indeed a 1-median of the cactus. Based on this condition, we localize the search for deriving a 1-median on the underlying cactus. Complexity analysis shows that the approach runs in linear time

Foci of Schistosomiasis mekongi, Northern Cambodia: II. Distribution of infection and morbidity.

In the province of Kracheh, in Northern Cambodia, a baseline epidemiological survey on Schistosoma mekongi was conducted along the Mekong River between December 1994 and April 1995. The results of household surveys of highly affected villages of the East and the West bank of the river and of school surveys in 20 primary schools are presented. In household surveys 1396 people were examined. An overall prevalence of infection of 49.3% was detected by a single stool examination with the Kato-Katz technique. The overall intensity of infection was 118.2 eggs per gram of stool (epg). There was no difference between the population of the east and west shore of the Mekong for prevalence (P = 0.3) or intensity (P = 0.9) of infection. Severe morbidity was very frequent. Hepatomegaly of the left lobe was detected in 48.7% of the population. Splenomegaly was seen in 26.8% of the study participants. Visible diverted circulation was found in 7.2% of the population, and ascites in 0.1%. Significantly more hepatomegaly (P = 0.001), splenomegaly (P = 0. 001) and patients with diverted circulation (P = 0.001) were present on the west bank of the Mekong. The age group of 10-14 years was most affected. The prevalence of infection in this group was 71.8% and 71.9% in the population of the West and East of the Mekong, respectively. The intensity of infection was 172.4 and 194.2 epg on the West and the East bank, respectively. In the peak age group hepatomegaly reached a prevalence of 88.1% on the west and 82.8% on the east bank. In the 20 schools 2391 children aged 6-16 years were examined. The overall prevalence of infection was 40.0%, ranging from 7.7% to 72.9% per school. The overalls mean intensity of infection was 110.1 epg (range by school: 26.7-187.5 epg). Both prevalence (P = 0.001) and intensity of infection (P = 0.001) were significantly higher in schools on the east side of the Mekong. Hepatomegaly (55.2%), splenomegaly (23.6%), diverted circulation (4. 1%), ascites (0.5%), reported blood (26.7%) and mucus (24.3%) were very frequent. Hepatomegaly (P = 0.001), splenomegaly (P = 0.001), diverted circulation (P = 0.001) and blood in stool (P = 0.001) were significantly more frequent in schools of the east side of the Mekong. Boys suffered more frequently from splenomegaly (P = 0.05), ascites (P = 0.05) and bloody stools (P = 0.004) than girls. No difference in sex was found for the prevalence and intensity of infection and prevalence of hepatomegaly. On the school level prevalence and intensity of infection were highly associated (r = 0. 93, P = 0.0001). The intensity of infection was significantly associated only with the prevalence of hepatomegaly (r = 0.44, P = 0. 05) and blood in stool (r = 0.40, P = 0.02). This comprehensive epidemiological study documents for the first time the public health importance of schistosomiasis mekongi in the Province of Kracheh, Northern Cambodia and points at key epidemiological features of this schistosome species, in particular the high level of morbidity associated with infection

Limits and dynamics of stochastic neuronal networks with random heterogeneous delays

Realistic networks display heterogeneous transmission delays. We analyze here the limits of large stochastic multi-populations networks with stochastic coupling and random interconnection delays. We show that depending on the nature of the delays distributions, a quenched or averaged propagation of chaos takes place in these networks, and that the network equations converge towards a delayed McKean-Vlasov equation with distributed delays. Our approach is mostly fitted to neuroscience applications. We instantiate in particular a classical neuronal model, the Wilson and Cowan system, and show that the obtained limit equations have Gaussian solutions whose mean and standard deviation satisfy a closed set of coupled delay differential equations in which the distribution of delays and the noise levels appear as parameters. This allows to uncover precisely the effects of noise, delays and coupling on the dynamics of such heterogeneous networks, in particular their role in the emergence of synchronized oscillations. We show in several examples that not only the averaged delay, but also the dispersion, govern the dynamics of such networks.Comment: Corrected misprint (useless stopping time) in proof of Lemma 1 and clarified a regularity hypothesis (remark 1

Assessment of the Effectiveness of Ich Tam Khang as a Supportive Therapy for Chronic Heart Failure

Background: Heart failure is a chronic disease needing lifelong management. Despite the advances that have been made in the treatment of the disease, both the longevity and quality of life for those with chronic heart failure remain impaired. A more effective therapeutic approach with less negative side effects is still needed. In this study, we evaluate Ich Tam Khang (ITK), the poly-ingredient herbal and nutritional preparation with multiple physiological actions, as a supportive therapy for patients with chronic heart failure.Aims of Study: To evaluate the effectiveness and safety of Ich Tam Khang as an adjunctive treatment of chronic heart failure.Methods: A total of 60 patients with chronic congestive heart failure were enrolled in this open label, cross-sectional and prospective study. All patients were treated with a conventional regimen (digoxin, diuretics, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), beta blockers) for at least 4 weeks before being divided into two equal groups. In the treated patients with ITK, patients received conventional therapy plus 4 tablets ITK per day added in two divided doses. In the control patients, all patients kept the same conventional regimen without ITK. All patients were followed up for 3 months for clinical and para-clinical outcomes.Result: The symptoms of heart failure (dyspnea, palpitation, peripheral edema, neck vein distention, heptojugular reflex) decreased. Heart rate and blood pressure stabilized during treatment in the treated patients with ITK. Additionally, total cholesterol and HDL-cholesterol normalized in the patients treated with ITK. Most of echocardiography parameters in the ITK treated patients were superior to the control patients. ITK is safe and it has no side effects.Conclusion: ITK as a combination of herbal and nutritional preparation is effective in reducing heart failure symptoms, improving patient's quality of life for the patients with decompensated heart failure and reducing total cholesterol and LDL-C

Dust extinction from Balmer decrements of star-forming galaxies at 0.75<z<1.5 with HST/WFC3 spectroscopy from the WISP survey

Spectroscopic observations of Halpha and Hbeta emission lines of 128 star-forming galaxies in the redshift range 0.75<z<1.5 are presented. These data were taken with slitless spectroscopy using the G102 and G141 grisms of the Wide-Field-Camera 3 (WFC3) on board the Hubble Space Telescope as part of the WFC3 Infrared Spectroscopic Parallel (WISP) survey. Interstellar dust extinction is measured from stacked spectra that cover the Balmer decrement (Halpha/Hbeta). We present dust extinction as a function of Halpha luminosity (down to 3 x 10^{41} erg/s), galaxy stellar mass (reaching 4 x 10^{8} Msun), and rest-frame Halpha equivalent width. The faintest galaxies are two times fainter in Halpha luminosity than galaxies previously studied at z~1.5. An evolution is observed where galaxies of the same Halpha luminosity have lower extinction at higher redshifts, whereas no evolution is found within our error bars with stellar mass. The lower Halpha luminosity galaxies in our sample are found to be consistent with no dust extinction. We find an anti-correlation of the [OIII]5007/Halpha flux ratio as a function of luminosity where galaxies with L_{Halpha}<5 x 10^{41} erg/s are brighter in [OIII]5007 than Halpha. This trend is evident even after extinction correction, suggesting that the increased [OIII]5007/Halpha ratio in low luminosity galaxies is likely due to lower metallicity and/or higher ionization parameters.Comment: 11 pages, 9 figures, 2 tables; version addressing the referee comment

BET proteins are associated with the induction of small airway fibrosis in COPD.

RationaleIn COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.ObjectivesDetermine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).MethodsPrimary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.Measurements and main resultsCOPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC.ConclusionsBET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny