Use of green manures & cover crops for the south

TypescriptM.S. University of Missouri 1907The problem of restoring the fertility to the worn soils and of maintaining that of the new or fresh soils is perhaps the most serious one with which the farmers of the cotton states are confronted. It is indeed unfortunate that the usual methods and practices of cotton farming tend to rapidly wear out and destroy the fertility of the soil, and before we can be safe and permanently prosperous in farming, our methods and practices must be such as to result in increasing the productiveness of our soils. The original fertility of a soil is dependent upon two things, viz: its natural strength and its physical condition. The first of these - the natural strength, is determined by the readiness with which the insoluble plant food in a soil becomes available by natural agencies, and the length of time this availability will continue. While the physical condition is dependent upon such properties as favor the growth and development of plant roots and the acquisition by these of the available plant food in the soil. The natural strength of a soil may be practically exhaustible and at the same time the fertility of the soil very low, on account of its poor physical condition. And a good soil in a good physical condition easily reduced to one of poor condition by improper handling. This last is true of almost all of the soils of the South. There are few cultivated soils of this section that have not suffered a material loss of plant food, while their once favorable physical condition is changed to such an extent as to reduce their productiveness. It remains for succeeding farmers to restore the once favorable conditions of our soils, and gain for the South its deserved recognition as a fertile and productive region, or to continue the wasteful and exhaustive methods of the past and produce a section whose chief glory will rest in the legends of a once fertile soil. Nature, it would seem on the one hand with its warm climate, its abundant rainfall, its loose and broken soils, and its seemingly careless farmers, cateIncludes bibliographical reference

The hERG1 (KV11.1) potassium channel : its modulation and the functional characterisation of genetic variants

The human ether á-go-go related gene (hERG1 or KCNH2) encodes the pore forming subunit of the cardiac delayed rectifier potassium (IKr) channel. Its unique kinetics result in a resurgent current crucial for the repolarisation of the cardiac action potential and a capability to suppress premature excitation. hERG1 is widely expressed with roles e.g. in neuronal firing, intestinal and uterine contractility, and insulin secretion. Furthermore overexpression and ectopic expression of hERG1 occurs in cancer where it is involved in proliferation, migration, chemotherapy resistance etc. The long QT syndrome (LQTS) often presents as sudden cardiac death in children and young adults. LQTS is characterised by electrocardiogram abnormalities with arrhythmia that can lead to palpitations, syncope, seizure, cardiac arrest and death. Underlying the congenital form of LQTS are mutations in ion channel proteins (including hERG1, the loss-of-function of which gives rise to LQT2) and their interacting proteins. Carriers of a particular mutation may be symptomatic (to varying extents) or asymptomatic, with the deleterious effects only emerging due to the presence of other factors. This is analogous to drug-induced LQTS where arrhythmia may occur in 1 of 120,000 users of certain non-cardiac drugs. Virtually all drug-induced LQTS is caused by inhibition of hERG1. Consequently in the field of safety pharmacology the hERG1 channel has for the last 20 years and continues to have a huge impact as the primary in vitro predictor of the proarrhythmic risk for a drug. Various aspects of the hERG1 channel are investigated in the studies presented in this thesis. The effect of prucalopride, a gastrointestinal prokinetic drug, on hERG1 was examined. Prucalopride exhibited rapid state and concentration dependent inhibition of hERG1 however, at therapeutic concentrations block is insignificant (hERG safety margin of ≥300). This in vitro prediction has translated to the clinical studies of this drug and the market. The heterogeneous phenotype associated with LQTS may arise from genetic modifiers such polymorphisms and mutations. Heterologous expression of the prevalent hERG1 K897T polymorphism identified a reduced hERG1 current density as the primary difference from wild-type, a result of decreased protein expression. Additionally a slowing of deactivation and alteration of inactivation was evident. Also studied but using induced pluripotent stem cell (iPSC) derived cardiomyocytes was hERG1 R176W. Unlike previous LQT2 iPSC models the origin here was a relatively asymptomatic individual. The phenotypic characteristics of LQT2 were however still reproduced in vitro (i.e. a decrease in IKr and action potential prolongation) though as a milder version. Finally the effect of ceramide, a sphingolipid which accumulates in heart failure and is involved in lipotoxicity, on hERG1 was investigated. Ceramide was found to reduce hERG1 current in a time dependent manner through tagging (ubiquitination) of the cell surface protein for internalisation and targeting to lysosomes.HERG (human ether-a-go-go related gene, hERG1 tai KCNH2) geenin ilmentämä proteiini tuottaa kaliumkanavan, joka vastaa sydänsolujen sähköfysiologisissa mittauksissa kuvattua IKr virtaa. HERG kaliumkanava aukeaa sydämen aktiopotentiaalin repolarisaatiovaiheessa ja estää näin ennenaikaisen aktiopotentiaalin laukeamisen. hERG1 proteiinia ilmentyy sydämen lisäksi useissa muissa kudoksissa mm. hermosoluissa, suolessa, kohdussa ja haiman insuliinia tuottavissa soluissa. hERG1 ilmentyy lisäksi useissa eri syöpäsoluissa, joissa se osallistuu syöpäsolujen jakautumisen säätelyyn, etäpesäkkeiden syntymiseen ja kemoterapiaresistenssin muodostumiseen. Pitkä QT-oireyhtymä on harvinainen perinnöllinen sairaus, joka ilmentyy lasten ja nuorten aikuisten sydänperäisenä äkkikuolemana. Pitkä QT-oireyhtymä voidaan tunnistaa sydänsähkökäyrästä kääntyvien kärkien kammiotakykardiana. Pitkä QT-oireyhtymän oireita ovat tajuttomuus, epilepsia, sydänpysähdys ja äkkikuolema. Geneettisten tutkimusten ansiosta tiedetään että perinnöllisen pitkä-QT oireyhtymän alaluokka LQT2 johtuu joko HERG geenin mutaatioista tai sen kanssa vuorovaikuttavien proteiinien mutaatioista. HERG mutaatioiden kantajat voivat olla täysin oireettomia mutta haitalliset henkeä uhkaavat vaikutukset saattavat tulla esille muiden tekijöiden vaikutuksesta. Joidenkin lääkkeiden erittäin harvinaisena haittavaikutuksena ilmentyvä rytmihäiriö on analoginen pitkä QT-oireyhtymän kanssa. Lääkeen aiheuttaman rytmihäiriön esiintyvyys on 1:120 000 tiettyjen muiden kuin sydänlääkkeiden lääkkeiden käyttäjistä. Käytännössä lähes kaikki lääkkeiden aiheuttamat sydämen rytmihäiriöt aiheutuvat HERG kaliumkanavan salpauksesta. Sen takia ei ole sattumaa että lääketeollisuuden varhainen lääketurvallisuutta ennustava tutkimus on siirtynyt laaja-alaisesti käyttämään HERG kaliumkanavan sähköfysiologisia mittauksia entistäkin turvallisempien lääkemolekyylien seulomiseksi ja kehittämiseksi lääkkeeksi asti. Tässä väitöskirjassa on tutkittu hERG1 kaliumkanavaa useasta eri lähtökohdasta käsin. Ensimäisessä julkaisussa kyettiin osoittamaan sähköfysiologisin in vitro mittauksin että ummetuksen hoitoon kehitetty lääke prucalopride salpasi hERG1 kaliumkanavaa vasta yli 300-kertaa suuremmissa pitoisuuksissa kuin mitä tarvitaan lääkkeen kliinisen tehon esille saamiseksi. Näin ollen in vitro mittauksin kyettiin ennustamaan että lääkkeellä on äärimmäisen pieni riski aihuttaa sydänperäisiä oireita, joka on sittemmin näytetty toteen kliinisissä tutkimuksissa. Toisessa julkaisussa tutkittiin pitkä-QT oireyhtymään liittyvää vaihtelevaa sähköfysiologista ilmiasua, joka voi aiheutua joko HERG geenin mutaatioista tai monimuotoisuudesta. HERG geenin K897T monimuotoinen versio vähensi solumallissa HERG proteiinin määrää verrattuna valtamutaatioon. Lisäksi monimuotoisen ionikanavan aukeamisen ja sulkeutumisen nopeus erosi valtamutaatiosta. Kolmannessa julkaisussa tutkittiin uudelleenohjelmoidussa sydänkantasolumallissa (iPS kardiomyosyytti) HERG proteiinin R176W monimuotoista versiota, joka oli peräisin melko oireettomalta henkilöltä. Pitkä QT-oireyhtymän ilmiasu (sydänsolun IKr virran väheneminen ja aktiopotentiaalin keston piteneminen) tuli esille sykkivien uudelleenohjelmoitujen sydänkantasolujen sähköfysiologisissa mittauksissa. Viimeisessä julkaisussa tutkittiin miten sydämen vajaatoiminnan aikana sydänlihakseen kertyvä sfingolipidi keramidi vaikuttaa HERG kaliumkanavan toimintaan. Osoittautui että keramidi vähensi HERG ionivirtaa ajasta riippuvasti, jolloin solukalvolla oleva HERG proteiini leimattiin ubikitiinillä solun sisälle lysosomiin hajotettavaksi

An inverse oblique effect in human vision

AbstractIn the classic oblique effect contrast detection thresholds, orientation discrimination thresholds, and other psychophysical measures are found to be smallest for vertical or horizontal stimuli and significantly higher for stimuli near the ±45° obliques. Here we report a novel inverse oblique effect in which thresholds for detecting translational structure in random dot patterns [Glass, L. (1969). Moiré effect from random dots. Nature, 223, 578–580] are lowest for obliquely oriented structure and higher for either horizontal or vertical structure. Area summation experiments provide evidence that this results from larger pooling areas for oblique orientations in these patterns. The results can be explained quantitatively by a model for complex cells in which the final filtering stage in a filter–rectify–filter sequence is of significantly larger area for oblique orientations

Virgin Birth in a Hammerhead Shark

Parthenogenesis has been documented in all major jawed vertebrate lineages except mammals and cartilaginous fishes (class Chondrichthyes: sharks, batoids and chimeras). Reports of captive female sharks giving birth despite being held in the extended absence of males have generally been ascribed to prior matings coupled with long-term sperm storage by the females. Here, we provide the first genetic evidence for chondrichthyan parthenogenesis, involving a hammerhead shark (Sphyrna tiburo). This finding also broadens the known occurrence of a specific type of asexual development (automictic parthenogenesis) among vertebrates, extending recently raised concerns about the potential negative effect of this type of facultative parthenogenesis on the genetic diversity of threatened vertebrate species

Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture

Peer reviewe

At Home in the Neolithic : Understanding Diversity in Neolithic Houses and Households

In the Editorial for the special edition on Neolithic Housesholds, we introduce the history of house and household studies in European Neolithic Archaeology and outline the papers in this collection

Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity

BACKGROUND AND PURPOSE: The lack of selective sodium-calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1 inhibitor. EXPERIMENTAL APPROACH: A flavan series-based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM-11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM-11372 were studied in normal and infarcted rats and rabbits. Human cardiac safety was studied ex vivo using human ventricular trabeculae. KEY RESULTS: ORM-11372 inhibited human NCX 1.1 reverse and forward currents; IC(50) values were 5 and 6 nM respectively. ORM-11372 inhibited human cardiac sodium 1.5 (I(Na) ) and hERG K(V) 11.1 currents (I(hERG) ) in a concentration-dependent manner; IC(50) values were 23.2 and 10.0 μM. ORM-11372 caused no changes in action potential duration; short-term variability and triangulation were observed for concentrations of up to 10 μM. ORM-11372 induced positive inotropic effects of 18 ± 6% and 35 ± 8% in anaesthetized rats with myocardial infarctions and in healthy rabbits respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose. CONCLUSION AND IMPLICATIONS: ORM-11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro-arrhythmic risk.Peer reviewe

Discovery and Characterization of ORM‐11372, a Novel Inhibitor of the Sodium‐Calcium Exchanger with Positive Inotropic Activity

Background and purpose The lack of selective sodium‐calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1. inhibitor. Experimental approach A flavan series‐based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM‐11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM‐11372 were studied in normal and infarcted rats, and rabbits. Human cardiac safety was studied ex‐vivo using human ventricular trabeculae. Key results ORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM, respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (INa) and hERG KV11.1 currents (IhERG) in a concentration‐dependent manner; IC50 values were 23.2 and 10.0 μM. ORM‐11372 caused no changes in action potential duration; short term variability and triangulation were observed for concentrations of upto 10 μM. ORM‐11372 induced positive inotropic effects in 18 ± 6% and 35 ± 8% anesthetized rats with myocardial infarctions and rabbits, respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose. Conclusion and implications ORM‐11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or blood pressure, without pro‐arrhythmic risk